start-ver=1.4
cd-journal=joma
no-vol=
cd-vols=
no-issue=
article-no=
start-page=
end-page=
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2026
dt-pub=20260521
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Stimulator of interferon genes agonist augmented antitumor immunity of osimertinib in                    <i>Egfr</i>                    ‐mutated lung cancer
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancers (NSCLCs) lack effective immunotherapy due to a noninflamed tumor microenvironment (TME). We previously reported that EGFR tyrosine-kinase-inhibitor (TKI) induced CD8+ T-cell immunity, which was insufficient for tumor eradication. We evaluated the potential of combining EGFR-TKI with stimulator of interferon genes (STING) agonists in activating a systemic antitumor response. Using a syngeneic mouse model of genetically engineered Egfr-mutant NSCLC, we evaluated the antitumor effects of STING agonist ADU-S100, alone and combined with osimertinib. Immunohistochemistry and flow cytometry were used to assess the TME. Osimertinib alone enhanced CD8+ T-cell infiltration but not Natural Killer (NK) cell infiltration. ADU-S100 injection alone modestly suppressed tumor growth with increasing CD8+/NK cell infiltration in the TME, but lacked an abscopal effect. Combining ADU-S100 with osimertinib significantly enhanced the antitumor effects and CD8+/NK cell infiltration. Depletion of either CD8+ or NK cells reduced the combination effect. Crucially, the combination induced an abscopal effect accompanied by PD-1+/CD8+ cell infiltration. Combining osimertinib with a STING agonist augmented innate and adaptive immunity, inducing systemic antitumor responses in EGFR-mutant NSCLC.
en-copyright=
kn-copyright=

en-aut-name=NishimuraJun
en-aut-sei=Nishimura
en-aut-mei=Jun
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=KuribayashiTadahiro
en-aut-sei=Kuribayashi
en-aut-mei=Tadahiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=BrägelmannJohannes
en-aut-sei=Brägelmann
en-aut-mei=Johannes
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=OkawaSachi
en-aut-sei=Okawa
en-aut-mei=Sachi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=TaokaMasataka
en-aut-sei=Taoka
en-aut-mei=Masataka
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=MoriShunta
en-aut-sei=Mori
en-aut-mei=Shunta
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=NishimuraTomoka
en-aut-sei=Nishimura
en-aut-mei=Tomoka
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=TanakaTakaaki
en-aut-sei=Tanaka
en-aut-mei=Takaaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=MakimotoGo
en-aut-sei=Makimoto
en-aut-mei=Go
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

en-aut-name=NinomiyaKiichiro
en-aut-sei=Ninomiya
en-aut-mei=Kiichiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=10
ORCID=

en-aut-name=RaiKammei
en-aut-sei=Rai
en-aut-mei=Kammei
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=11
ORCID=

en-aut-name=IchiharaEiki
en-aut-sei=Ichihara
en-aut-mei=Eiki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=12
ORCID=

en-aut-name=KatayamaRyohei
en-aut-sei=Katayama
en-aut-mei=Ryohei
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=13
ORCID=

en-aut-name=HottaKatsuyuki
en-aut-sei=Hotta
en-aut-mei=Katsuyuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=14
ORCID=

en-aut-name=TabataMasahiro
en-aut-sei=Tabata
en-aut-mei=Masahiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=15
ORCID=

en-aut-name=TogashiYosuke
en-aut-sei=Togashi
en-aut-mei=Yosuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=16
ORCID=

en-aut-name=MaedaYoshinobu
en-aut-sei=Maeda
en-aut-mei=Yoshinobu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=17
ORCID=

en-aut-name=SosMartin L.
en-aut-sei=Sos
en-aut-mei=Martin L.
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=18
ORCID=

en-aut-name=KiuraKatsuyuki
en-aut-sei=Kiura
en-aut-mei=Katsuyuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=19
ORCID=

en-aut-name=OhashiKadoaki
en-aut-sei=Ohashi
en-aut-mei=Kadoaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=20
ORCID=

affil-num=1
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=2
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=3
en-affil=Department of Translational Genomics Faculty of Medicine and University Hospital Cologne, University of Cologne  Germany
kn-affil=

affil-num=4
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=5
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=6
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=7
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=8
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=9
en-affil=Department of Respiratory Medicine, Okayama University Hospital
kn-affil=

affil-num=10
en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital
kn-affil=

affil-num=11
en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital
kn-affil=

affil-num=12
en-affil=Center for Clinical Oncology, Okayama University Hospital
kn-affil=

affil-num=13
en-affil=Division of Experimental Chemotherapy, Cancer Chemotherapy Centre, Japanese Foundation for Cancer Research
kn-affil=

affil-num=14
en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital
kn-affil=

affil-num=15
en-affil=Center for Clinical Oncology, Okayama University Hospital
kn-affil=

affil-num=16
en-affil=Department of Respiratory Medicine, Okayama University Hospital
kn-affil=

affil-num=17
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=18
en-affil=Department of Translational Genomics Faculty of Medicine and University Hospital Cologne, University of Cologne  Germany
kn-affil=

affil-num=19
en-affil=Department of Respiratory Medicine, Okayama University Hospital
kn-affil=

affil-num=20
en-affil=Department of Respiratory Medicine, Okayama University Hospital
kn-affil=
en-keyword=abscopal effect
kn-keyword=abscopal effect
en-keyword=CD8+ T cells
kn-keyword=CD8+ T cells
en-keyword=EGFR mutation
kn-keyword=EGFR mutation
en-keyword=EGFR tyrosine kinase inhibitor
kn-keyword=EGFR tyrosine kinase inhibitor
en-keyword=NK cells
kn-keyword=NK cells
en-keyword=stimulator of interferon genes
kn-keyword=stimulator of interferon genes
END

start-ver=1.4
cd-journal=joma
no-vol=
cd-vols=
no-issue=
article-no=
start-page=1
end-page=17
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2026
dt-pub=20260601
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Afatinib Overcomes Osimertinib Resistance via Egfr V804F Mutation in a Syngeneic Egfr-Mutant Lung Cancer Mouse Model
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Osimertinib is the standard first-line treatment for advanced EGFR-mutant non-small cell lung cancer. However, acquired resistance invariably develops, and identifying novel resistance pathways is clinically important as a substantial portion remains undefined. We used an immunocompetent syngeneic lung cancer mouse model harboring an Egfr exon 19 deletion (mDEL tumors) to establish acquired resistance. Osimertinib-resistant tumors were generated in vivo using a drug-holiday/re-challenge protocol. The resistance mechanism was identified using Sanger sequencing, receptor tyrosine kinase arrays, and western blotting. Egfr V804F knock-in cells were generated using CRISPR/Cas9, and their sensitivity to osimertinib and afatinib was assessed in vitro and in vivo. We established two distinct osimertinib-resistant tumor lines in a syngeneic lung cancer mouse model (mDEL OsiR #1/#3). The analysis revealed an on-target secondary Egfr V804F mutation (corresponding to human EGFR V802F) in both tumor lines. Importantly, Egfr V804F knock-in cells demonstrated significant osimertinib resistance, with a 5.7–10.5-fold increase in in vitro IC50 (mean, 8.2-fold), but remained highly sensitive to afatinib. Furthermore, afatinib effectively overcame osimertinib resistance in the V804F knock-in cell-derived mouse model. Consistently, afatinib treatment resulted in marked tumor shrinkage and suppression of EGFR signaling in the established mDEL OsiR #1/#3 in vivo. These findings establish secondary Egfr V804F/EGFR V802F as an on-target osimertinib resistance mechanism, providing a preclinical rationale for evaluating afatinib in biomarker-selected patients harboring this alteration.
en-copyright=
kn-copyright=

en-aut-name=TanakaTakaaki
en-aut-sei=Tanaka
en-aut-mei=Takaaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=FujitaniMasato
en-aut-sei=Fujitani
en-aut-mei=Masato
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=TaokaMasataka
en-aut-sei=Taoka
en-aut-mei=Masataka
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=ShimomuraIwao
en-aut-sei=Shimomura
en-aut-mei=Iwao
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=OkawaSachi
en-aut-sei=Okawa
en-aut-mei=Sachi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=MoriShunta
en-aut-sei=Mori
en-aut-mei=Shunta
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=KuribayashiTadahiro
en-aut-sei=Kuribayashi
en-aut-mei=Tadahiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=NishimuraJun
en-aut-sei=Nishimura
en-aut-mei=Jun
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=NishimuraTomoka
en-aut-sei=Nishimura
en-aut-mei=Tomoka
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

en-aut-name=MoritaAyako
en-aut-sei=Morita
en-aut-mei=Ayako
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=10
ORCID=

en-aut-name=HaraNaofumi
en-aut-sei=Hara
en-aut-mei=Naofumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=11
ORCID=

en-aut-name=NinomiyaKiichiro
en-aut-sei=Ninomiya
en-aut-mei=Kiichiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=12
ORCID=

en-aut-name=MakimotoGo
en-aut-sei=Makimoto
en-aut-mei=Go
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=13
ORCID=

en-aut-name=HigoHisao
en-aut-sei=Higo
en-aut-mei=Hisao
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=14
ORCID=

en-aut-name=RaiKammei
en-aut-sei=Rai
en-aut-mei=Kammei
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=15
ORCID=

en-aut-name=IchiharaEiki
en-aut-sei=Ichihara
en-aut-mei=Eiki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=16
ORCID=

en-aut-name=TomidaShuta
en-aut-sei=Tomida
en-aut-mei=Shuta
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=17
ORCID=

en-aut-name=HottaKatsuyuki
en-aut-sei=Hotta
en-aut-mei=Katsuyuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=18
ORCID=

en-aut-name=TogashiYosuke
en-aut-sei=Togashi
en-aut-mei=Yosuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=19
ORCID=

en-aut-name=MaedaYoshinobu
en-aut-sei=Maeda
en-aut-mei=Yoshinobu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=20
ORCID=

en-aut-name=KiuraKatsuyuki
en-aut-sei=Kiura
en-aut-mei=Katsuyuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=21
ORCID=

en-aut-name=KatayamaRyohei
en-aut-sei=Katayama
en-aut-mei=Ryohei
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=22
ORCID=

en-aut-name=OhashiKadoaki
en-aut-sei=Ohashi
en-aut-mei=Kadoaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=23
ORCID=

affil-num=1
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=2
en-affil=Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research
kn-affil=

affil-num=3
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=4
en-affil=Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research
kn-affil=

affil-num=5
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=6
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=7
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=8
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=9
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=10
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University
kn-affil=

affil-num=11
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University
kn-affil=

affil-num=12
en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital
kn-affil=

affil-num=13
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University
kn-affil=

affil-num=14
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University
kn-affil=

affil-num=15
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University
kn-affil=

affil-num=16
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University
kn-affil=

affil-num=17
en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital
kn-affil=

affil-num=18
en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital
kn-affil=

affil-num=19
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University
kn-affil=

affil-num=20
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=21
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University
kn-affil=

affil-num=22
en-affil=Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research
kn-affil=

affil-num=23
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University
kn-affil=
en-keyword=afatinib
kn-keyword=afatinib
en-keyword=EGFR-mutant NSCLC
kn-keyword=EGFR-mutant NSCLC
en-keyword=exon 19 deletion
kn-keyword=exon 19 deletion
en-keyword=osimertinib resistance
kn-keyword=osimertinib resistance
en-keyword=V802F (human EGFR)/V804F (murine Egfr)
kn-keyword=V802F (human EGFR)/V804F (murine Egfr)
END

start-ver=1.4
cd-journal=joma
no-vol=75
cd-vols=
no-issue=4
article-no=
start-page=121
end-page=
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2026
dt-pub=20260324
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Immunological effects of amivantamab in EGFR or MET-expressing non-small cell lung cancer
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Background Epidermal growth factor receptor (EGFR) mutations represent one of the most frequent oncogenic driver in non-small cell lung cancer (NSCLC). Amivantamab, a bispecific antibody targeting EGFR and MET proto-oncogene, receptor tyrosine kinase (MET), has demonstrated clinical benefit in EGFR-mutant NSCLC through dual blockade, but its immunological role in human clinical specimens, especially tumor-infiltrating lymphocytes (TILs), has not been directly evaluated.<br>
Methods We analyzed surgically resected tumor samples from 40 patients with NSCLC to investigate immune responses and their associations with EGFR and MET expression. TILs were characterized by flow cytometry (FCM) and immunohistochemistry (IHC). To assess the immunomodulatory potential of amivantamab, fresh tumor digests containing live tumor cells and TILs were cultured ex vivo with CD3 and CD28 stimulation in the absence or presence of amivantamab, followed by FCM. EGFR and MET expression were also evaluated by IHC.<br>
Results EGFR mutations and high EGFR protein expression were associated with a trend toward reduced CD8⁺ T-cell and dendritic cell (DC) infiltration. In ex vivo TIL assays, exposure to amivantamab significantly activated CD8⁺ T cells, such as programmed cell death-1 expression and cytokine production, and promoted DC maturation. These effects were most pronounced in tumors with high EGFR or MET protein expression rather than EGFR mutations.<br>
Conclusions This study provides the first direct evidence from ex vivo fresh TIL assays using human NSCLC clinical specimens that amivantamab can activate immune responses. EGFR and MET expression may serve as potential biomarkers for amivantamab-induced immune responses.
en-copyright=
kn-copyright=

en-aut-name=YoshichikaRyo
en-aut-sei=Yoshichika
en-aut-mei=Ryo
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=MukoharaFumiaki
en-aut-sei=Mukohara
en-aut-mei=Fumiaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=YamadaKotaro
en-aut-sei=Yamada
en-aut-mei=Kotaro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=NagasakiJoji
en-aut-sei=Nagasaki
en-aut-mei=Joji
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=WatanabeHiroko
en-aut-sei=Watanabe
en-aut-mei=Hiroko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=UedaYouki
en-aut-sei=Ueda
en-aut-mei=Youki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=SuzawaKen
en-aut-sei=Suzawa
en-aut-mei=Ken
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=ShienKazuhiko
en-aut-sei=Shien
en-aut-mei=Kazuhiko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=ToyookaShinichi
en-aut-sei=Toyooka
en-aut-mei=Shinichi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

en-aut-name=IshinoTakamasa
en-aut-sei=Ishino
en-aut-mei=Takamasa
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=10
ORCID=

en-aut-name=TogashiYosuke
en-aut-sei=Togashi
en-aut-mei=Yosuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=11
ORCID=

affil-num=1
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=2
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=3
en-affil=Department of Respiratory Medicine, Okayama University Hospital
kn-affil=

affil-num=4
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=5
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=6
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=7
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama University
kn-affil=

affil-num=8
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama University
kn-affil=

affil-num=9
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama University
kn-affil=

affil-num=10
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=11
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=
en-keyword=Non-small cell lung cancer
kn-keyword=Non-small cell lung cancer
en-keyword=Amivantamab
kn-keyword=Amivantamab
en-keyword=Antitumor immunity
kn-keyword=Antitumor immunity
en-keyword=EGFR
kn-keyword=EGFR
en-keyword=MET
kn-keyword=MET
END

start-ver=1.4
cd-journal=joma
no-vol=117
cd-vols=
no-issue=5
article-no=
start-page=1260
end-page=1272
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2026
dt-pub=20260227
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=TGF-β Inhibitor Potentiates Osimertinib-Induced Anti-Tumor Immunity in Egfr-Mutant Lung Cancer
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Immunotherapy for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) remains challenging. We previously found that EGFR-tyrosine kinase inhibitors induced antitumor immunity but also triggered immunosuppressive cytokines, including transforming growth factor-β (TGF-β), in Egfr-mutant lung cancer. Here, we investigate whether TGF-β inhibition potentiates osimertinib-induced antitumor immunity using a syngeneic mouse model of Egfr-mutated lung cancer, with cancer cells subcutaneously transplanted into wild-type C57BL/6J mice. We evaluated the antitumor effect of the combination therapy with osimertinib and either nintedanib (an indirect TGF-β inhibitor) or vactosertib (a specific TGF-β type I receptor kinase inhibitor). Changes in the tumor microenvironment during treatment were assessed using immunohistochemical staining, western blot analysis, and flow cytometry. We found that TGF-β expression was upregulated in the tumor treated with osimertinib. Nintedanib monotherapy showed no significant antitumor effect, whereas osimertinib combined with nintedanib significantly potentiates the antitumor effect compared with osimertinib monotherapy in vivo. Crucially, no additive effect of nintedanib on osimertinib monotherapy was observed in vitro. Combination therapy with osimertinib and nintedanib significantly increased effector T cells (CD8+CD44+CD62L−) and Granzyme B+ areas and decreased CD206+ cells, while significantly decreasing TGF-β and SMAD2/3 expression. Similar effects were observed with vactosertib but not with a vascular endothelial growth factor receptor 2 inhibitor. In conclusion, combination therapy with osimertinib and TGF-β inhibitors potentiates osimertinib-induced antitumor immunity. These findings highlight a novel therapeutic strategy for EGFR-mutated NSCLC and warrant further clinical investigation.
en-copyright=
kn-copyright=

en-aut-name=KuribayashiTadahiro
en-aut-sei=Kuribayashi
en-aut-mei=Tadahiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=NishimuraJun
en-aut-sei=Nishimura
en-aut-mei=Jun
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=OkawaSachi
en-aut-sei=Okawa
en-aut-mei=Sachi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=TaokaMasataka
en-aut-sei=Taoka
en-aut-mei=Masataka
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=MoriShunta
en-aut-sei=Mori
en-aut-mei=Shunta
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=TanakaTakaaki
en-aut-sei=Tanaka
en-aut-mei=Takaaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=NishimuraTomoka
en-aut-sei=Nishimura
en-aut-mei=Tomoka
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=MoritaAyako
en-aut-sei=Morita
en-aut-mei=Ayako
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=HaraNaofumi
en-aut-sei=Hara
en-aut-mei=Naofumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

en-aut-name=NinomiyaKiichiro
en-aut-sei=Ninomiya
en-aut-mei=Kiichiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=10
ORCID=

en-aut-name=MakimotoGo
en-aut-sei=Makimoto
en-aut-mei=Go
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=11
ORCID=

en-aut-name=RaiKammei
en-aut-sei=Rai
en-aut-mei=Kammei
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=12
ORCID=

en-aut-name=IchiharaEiki
en-aut-sei=Ichihara
en-aut-mei=Eiki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=13
ORCID=

en-aut-name=HottaKatsuyuki
en-aut-sei=Hotta
en-aut-mei=Katsuyuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=14
ORCID=

en-aut-name=TogashiYosuke
en-aut-sei=Togashi
en-aut-mei=Yosuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=15
ORCID=

en-aut-name=MaedaYoshinobu
en-aut-sei=Maeda
en-aut-mei=Yoshinobu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=16
ORCID=

en-aut-name=KiuraKatsuyuki
en-aut-sei=Kiura
en-aut-mei=Katsuyuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=17
ORCID=

en-aut-name=OhashiKadoaki
en-aut-sei=Ohashi
en-aut-mei=Kadoaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=18
ORCID=

affil-num=1
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=2
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=3
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=4
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=5
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=6
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=7
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=8
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=9
en-affil=Department of Respiratory Medicine, Okayama University Hospital
kn-affil=

affil-num=10
en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital
kn-affil=

affil-num=11
en-affil=Department of Respiratory Medicine, Okayama University Hospital
kn-affil=

affil-num=12
en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital
kn-affil=

affil-num=13
en-affil=Center for Clinical Oncology, Okayama University Hospital
kn-affil=

affil-num=14
en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital
kn-affil=

affil-num=15
en-affil=Department of Respiratory Medicine, Okayama University Hospital
kn-affil=

affil-num=16
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=17
en-affil=Department of Respiratory Medicine, Okayama University Hospital
kn-affil=

affil-num=18
en-affil=Department of Respiratory Medicine, Okayama University Hospital
kn-affil=
en-keyword=EGFR
kn-keyword=EGFR
en-keyword=lung cancer
kn-keyword=lung cancer
en-keyword=nintedanib
kn-keyword=nintedanib
en-keyword=osimertinib
kn-keyword=osimertinib
en-keyword=TGF-β
kn-keyword=TGF-β
END

start-ver=1.4
cd-journal=joma
no-vol=40
cd-vols=
no-issue=6
article-no=
start-page=e70582
end-page=
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2026
dt-pub=20260528
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Risk Factors for Waiting List Mortality in Lung Transplant Candidates With Post‐Hematopoietic Stem Cell Transplantation Non‐Infectious Pulmonary Complications
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Background: Late-onset non-infectious pulmonary complications (LONIPCs) following hematopoietic stem cell transplantation (HSCT) are a known indication for need of lung transplantation. This study aimed to clarify the clinical characteristics of patients with LONIPCs after HSCT who were registered for lung transplantation and reveal the risk factors for waiting list mortality.<br>
Methods: We retrospectively reviewed the clinical data of patients with LONIPCs after allogeneic HSCT who were referred to Okayama University Hospital and registered in the Japan Organ Transplant Network for deceased-donor lung transplantation between 2005 and 2023. Pediatric patients aged <18 years at the time of registration were excluded.<br>
Results: Thirty-four patients were included in this study. Notably, two distinct phenotypic groups were identified: One with a bronchiolitis obliterans pattern on high-resolution computed tomography and a mixed ventilatory defect, and the other with a pleuroparenchymal fibroelastosis pattern and a restrictive ventilatory defect. The median waiting duration for a deceased-donor lung transplant was 662 days, and 16 patients died during the waiting period. The cumulative incidence of waiting list mortality was 20.6% (95% confidence interval [CI], 8.9%–35.6%) at 1 year and 46.1% (95% CI, 27.8%–62.7%) at 3 years. A history of pneumothorax, greater dyspnea on exertion, and higher serum Krebs von den Lungen-6 levels were associated with an increased risk of waiting list mortality.<br>
Conclusion: In patients with LONIPCs after HSCT, a history of pneumothorax may be a marker of a poor prognosis and could serve as a criterion for referral of lung transplantation.
en-copyright=
kn-copyright=

en-aut-name=HigoHisao
en-aut-sei=Higo
en-aut-mei=Hisao
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=SenooSatoru
en-aut-sei=Senoo
en-aut-mei=Satoru
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=MakimotoSatoko
en-aut-sei=Makimoto
en-aut-mei=Satoko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=NaganoTomohiro
en-aut-sei=Nagano
en-aut-mei=Tomohiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=KondoTakumi
en-aut-sei=Kondo
en-aut-mei=Takumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=YamamotoHaruchika
en-aut-sei=Yamamoto
en-aut-mei=Haruchika
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=TanakaShin
en-aut-sei=Tanaka
en-aut-mei=Shin
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=MiyoshiKentaroh
en-aut-sei=Miyoshi
en-aut-mei=Kentaroh
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=SugimotoSeiichiro
en-aut-sei=Sugimoto
en-aut-mei=Seiichiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

en-aut-name=ToyookaShinichi
en-aut-sei=Toyooka
en-aut-mei=Shinichi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=10
ORCID=

en-aut-name=MaedaYoshinobu
en-aut-sei=Maeda
en-aut-mei=Yoshinobu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=11
ORCID=

en-aut-name=TogashiYosuke
en-aut-sei=Togashi
en-aut-mei=Yosuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=12
ORCID=

en-aut-name=MiyaharaNobuaki
en-aut-sei=Miyahara
en-aut-mei=Nobuaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=13
ORCID=

affil-num=1
en-affil=Department of Respiratory Medicine, Okayama University Hospital
kn-affil=

affil-num=2
en-affil=Department of Respiratory Medicine, Okayama University Hospital
kn-affil=

affil-num=3
en-affil=Department of Radiology, Okayama University Hospital
kn-affil=

affil-num=4
en-affil=Department of Hematology, Okayama University Hospital
kn-affil=

affil-num=5
en-affil=Department of Hematology, Okayama University Hospital
kn-affil=

affil-num=6
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=7
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=8
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=9
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=10
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=11
en-affil=Department of Respiratory Medicine, Okayama University Hospital
kn-affil=

affil-num=12
en-affil=Department of Respiratory Medicine, Okayama University Hospital
kn-affil=

affil-num=13
en-affil=Department of Respiratory Medicine, Okayama University Hospital
kn-affil=
en-keyword=hematopoietic stem cell transplantation
kn-keyword=hematopoietic stem cell transplantation
en-keyword=late-onset non-infectious pulmonary complications
kn-keyword=late-onset non-infectious pulmonary complications
en-keyword=lung transplantation
kn-keyword=lung transplantation
en-keyword=pneumothorax
kn-keyword=pneumothorax
END

start-ver=1.4
cd-journal=joma
no-vol=
cd-vols=
no-issue=
article-no=
start-page=
end-page=
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2026
dt-pub=20260519
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Incidence of B-cell Malignancies in Patients with Lung Cancer Receiving PD-1 Blockade Therapy
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Purpose: Many patients with various cancer types have received immune checkpoint inhibitors (ICI) worldwide since their approval, and novel unexpected complications from their long-term use are apparent. We identified some cases of B-cell lymphoma occurring during PD-1 blockade therapy as such unexpected complications. In this study, we aimed to evaluate the incidence of hematologic malignancies in patients with lung cancer receiving PD-1 blockade therapy and to elucidate the mechanisms underlying the progression of these malignancies.<br>
Experimental Design: We performed IHC staining on the clinical samples from patients with B-cell lymphoma that developed during PD-1 blockade therapy and analyzed large-scale real-world datasets. We further investigated the underlying mechanisms through in vitro and in vivo experiments.<br>
Results: A higher incidence of B-cell malignancies has been observed in patients with lung cancer treated with PD-1 blockade therapies based on large-scale real-world data analyses (n = 15,670). The identified lymphomas had a large amount of CD4+ T follicular helper (TFH) cell infiltration. In addition, PD-1 blockade activated PD-1+ TFH cells, which promoted lymphoma proliferation via the IL4/IL4R, IL21/IL21R, and CD40L/CD40 axes. Notably, the lymphomas exhibited high expression of IL4R, IL21R, and CD40.<br>
Conclusions: Our findings highlight the need for careful monitoring and consideration of the potential B-cell malignancy complications in clinical settings in which ICIs are used.
en-copyright=
kn-copyright=

en-aut-name=NinomiyaToshifumi
en-aut-sei=Ninomiya
en-aut-mei=Toshifumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=FangCaiyang
en-aut-sei=Fang
en-aut-mei=Caiyang
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=HamanoHirofumi
en-aut-sei=Hamano
en-aut-mei=Hirofumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=MorinagaTeruya
en-aut-sei=Morinaga
en-aut-mei=Teruya
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=ZhouWenhao
en-aut-sei=Zhou
en-aut-mei=Wenhao
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=KoyamaToshihiro
en-aut-sei=Koyama
en-aut-mei=Toshihiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=MikiSakura
en-aut-sei=Miki
en-aut-mei=Sakura
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=ZhuLi
en-aut-sei=Zhu
en-aut-mei=Li
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=NaoiYusuke
en-aut-sei=Naoi
en-aut-mei=Yusuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

en-aut-name=EnnishiDaisuke
en-aut-sei=Ennishi
en-aut-mei=Daisuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=10
ORCID=

en-aut-name=KatsutaTomoya
en-aut-sei=Katsuta
en-aut-mei=Tomoya
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=11
ORCID=

en-aut-name=OhashiKadoaki
en-aut-sei=Ohashi
en-aut-mei=Kadoaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=12
ORCID=

en-aut-name=MorizaneShin
en-aut-sei=Morizane
en-aut-mei=Shin
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=13
ORCID=

en-aut-name=Ohki-IkedaTomoka
en-aut-sei=Ohki-Ikeda
en-aut-mei=Tomoka
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=14
ORCID=

en-aut-name=NishiTatsuya
en-aut-sei=Nishi
en-aut-mei=Tatsuya
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=15
ORCID=

en-aut-name=UedaYouki
en-aut-sei=Ueda
en-aut-mei=Youki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=16
ORCID=

en-aut-name=IshinoTakamasa
en-aut-sei=Ishino
en-aut-mei=Takamasa
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=17
ORCID=

en-aut-name=MaedaYoshinobu
en-aut-sei=Maeda
en-aut-mei=Yoshinobu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=18
ORCID=

en-aut-name=OkamotoIsamu
en-aut-sei=Okamoto
en-aut-mei=Isamu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=19
ORCID=

en-aut-name=ZamamiYoshito
en-aut-sei=Zamami
en-aut-mei=Yoshito
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=20
ORCID=

en-aut-name=NagasakiJoji
en-aut-sei=Nagasaki
en-aut-mei=Joji
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=21
ORCID=

en-aut-name=TogashiYosuke
en-aut-sei=Togashi
en-aut-mei=Yosuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=22
ORCID=

affil-num=1
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=2
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=3
en-affil=Department of Pharmacy, Okayama University Hospital, Okayama University
kn-affil=

affil-num=4
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=5
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=6
en-affil=Department of Pharmaceutical Data Science, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=7
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=8
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=9
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=10
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=11
en-affil=Department of Respiratory Medicine, Ehime Prefectural Central Hospital
kn-affil=

affil-num=12
en-affil=Department of Respiratory Medicine, Okayama University Hospital, Okayama University
kn-affil=

affil-num=13
en-affil=Department of Dermatology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=14
en-affil=Department of Pathology, Okayama University Hospital, Okayama University
kn-affil=

affil-num=15
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=16
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=17
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=18
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=19
en-affil=Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University
kn-affil=

affil-num=20
en-affil=Department of Pharmacy, Okayama University Hospital, Okayama University
kn-affil=

affil-num=21
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=22
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=
END

start-ver=1.4
cd-journal=joma
no-vol=6
cd-vols=
no-issue=2
article-no=
start-page=284
end-page=293
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2026
dt-pub=20260201
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Clinical Characteristics and Spatial Transcriptome Analysis of Non–Small Cell Lung Cancers Exhibiting Early Alectinib Resistance: A Retrospective OLCSG Study
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Some anaplastic lymphoma kinase (ALK) gene rearrangement–positive lung cancers show early resistance, within 3 months, to alectinib. This study investigated the clinical and molecular characteristics of these patients. We analyzed patients with unresectable stage III/IV disease without indications for radical radiotherapy and recurrent ALK-positive lung cancer who received alectinib as the primary ALK tyrosine kinase inhibitor between 2013 and 2021 at nine hospitals. In total, 103 patients were included. The median age was 65 years; 44 were male and 22 had brain metastases. The median progression-free survival and overall survival (OS) were 28.7 and 80.6 months. Nineteen patients treated for ≤3 months and 84 treated for >3 months were categorized into the early resistance and responder groups, respectively. The early resistance group had significantly shorter OS (8.4 months vs. not estimable, P < 0.001) and was significantly more likely to have brain metastases (42% vs. 17%, P = 0.027). They also showed elevated inflammatory markers, including neutrophil-to-lymphocyte ratio (NLR). Univariate analysis identified brain metastases and high NLR as significant predictors of early resistance. Spatial transcriptome analysis and immunohistochemical staining revealed upregulation of annexin A1 (ANXA1), a calcium-dependent phospholipid-binding protein involved in inflammation and cancer progression, in the early resistance group. Interleukin 6 stimulation, prompted by elevated inflammatory markers, increased ANXA1 expression and reduced alectinib sensitivity. Knockdown of ANXA1 improved alectinib sensitivity in alectinib-resistant cells. In conclusion, brain metastases and high NLR are associated with early resistance. ANXA1 may play an important role in mediating early resistance. New treatment options for the early resistance group are required.
en-copyright=
kn-copyright=

en-aut-name=KuribayashiTadahiro
en-aut-sei=Kuribayashi
en-aut-mei=Tadahiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=MakimotoGo
en-aut-sei=Makimoto
en-aut-mei=Go
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=OhashiKadoaki
en-aut-sei=Ohashi
en-aut-mei=Kadoaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=TomidaShuta
en-aut-sei=Tomida
en-aut-mei=Shuta
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=InoueHirofumi
en-aut-sei=Inoue
en-aut-mei=Hirofumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=YokoyamaToshihide
en-aut-sei=Yokoyama
en-aut-mei=Toshihide
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=KuyamaShoichi
en-aut-sei=Kuyama
en-aut-mei=Shoichi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=KatoYuka
en-aut-sei=Kato
en-aut-mei=Yuka
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=KudoKenichiro
en-aut-sei=Kudo
en-aut-mei=Kenichiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

en-aut-name=HoritaNaokatsu
en-aut-sei=Horita
en-aut-mei=Naokatsu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=10
ORCID=

en-aut-name=KayataniHiroe
en-aut-sei=Kayatani
en-aut-mei=Hiroe
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=11
ORCID=

en-aut-name=InoueMasaaki
en-aut-sei=Inoue
en-aut-mei=Masaaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=12
ORCID=

en-aut-name=SugimotoKeisuke
en-aut-sei=Sugimoto
en-aut-mei=Keisuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=13
ORCID=

en-aut-name=NinomiyaKiichiro
en-aut-sei=Ninomiya
en-aut-mei=Kiichiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=14
ORCID=

en-aut-name=MaedaYoshinobu
en-aut-sei=Maeda
en-aut-mei=Yoshinobu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=15
ORCID=

en-aut-name=TogashiYosuke
en-aut-sei=Togashi
en-aut-mei=Yosuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=16
ORCID=

en-aut-name=HottaKatsuyuki
en-aut-sei=Hotta
en-aut-mei=Katsuyuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=17
ORCID=

affil-num=1
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=2
en-affil=Department of Respiratory Medicine, Okayama University Hospital
kn-affil=

affil-num=3
en-affil=Department of Respiratory Medicine, Okayama University Hospital
kn-affil=

affil-num=4
en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital
kn-affil=

affil-num=5
en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital
kn-affil=

affil-num=6
en-affil=Department of Respiratory Medicine, Ohara Healthcare Foundation, Kurashiki Central Hospital
kn-affil=

affil-num=7
en-affil=Department of Respiratory Medicine, NHO Iwakuni Clinical Center
kn-affil=

affil-num=8
en-affil=Department of Thoracic Oncology and Medicine, National Hospital Organization, Shikoku Cancer Center
kn-affil=

affil-num=9
en-affil=Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center
kn-affil=

affil-num=10
en-affil=Department of Respiratory Medicine, Kure Kyosai Hospital
kn-affil=

affil-num=11
en-affil=Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital
kn-affil=

affil-num=12
en-affil=Department of Chest Surgery, Shimonoseki City Hospital
kn-affil=

affil-num=13
en-affil=Department of Respiratory Medicine, Japanese Red Cross Kobe Hospital
kn-affil=

affil-num=14
en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital
kn-affil=

affil-num=15
en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=16
en-affil=Department of Respiratory Medicine, Okayama University Hospital
kn-affil=

affil-num=17
en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital
kn-affil=
END

start-ver=1.4
cd-journal=joma
no-vol=45
cd-vols=
no-issue=1
article-no=
start-page=116781
end-page=
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2026
dt-pub=202601
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Immunopeptidomics combined with full-length transcriptomics uncovers diverse neoantigens
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Neoantigens are crucial for antitumor immunity and immune checkpoint inhibitor (ICI) efficacy by triggering strong immune responses. However, conventional methods for identifying neoantigens, such as whole-exon sequencing and short-read RNA sequencing (RNA-seq), appear to be insufficient, and the tumor mutational burden cannot sufficiently predict ICI efficacy. In this study, we employed a proteogenomic approach using long-read RNA-seq with Pacific Biosciences Single-Molecule Real-Time Sequencing technology to analyze full-length transcripts in combination with the human leukocyte antigen ligandome. As a result, many neoantigen candidates were identified, which were unregistered in a comprehensive database, including those from non-coding regions. Additionally, we validated the responses of specific T cell receptors (TCRs) to these candidates and identified several pairs of TCRs and neoantigens. These findings highlight the presence of more diverse neoantigens than expected that cannot be identified by conventional methods.
en-copyright=
kn-copyright=

en-aut-name=IshinoTakamasa
en-aut-sei=Ishino
en-aut-mei=Takamasa
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=WatanabeTomofumi
en-aut-sei=Watanabe
en-aut-mei=Tomofumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=TokitaSerina
en-aut-sei=Tokita
en-aut-mei=Serina
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=UedaYouki
en-aut-sei=Ueda
en-aut-mei=Youki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=KawaseKatsushige
en-aut-sei=Kawase
en-aut-mei=Katsushige
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=TakanoYuka
en-aut-sei=Takano
en-aut-mei=Yuka
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=ThuYin Min
en-aut-sei=Thu
en-aut-mei=Yin Min
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=SuzukiYuta
en-aut-sei=Suzuki
en-aut-mei=Yuta
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=OwaChie
en-aut-sei=Owa
en-aut-mei=Chie
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

en-aut-name=InozumeTakashi
en-aut-sei=Inozume
en-aut-mei=Takashi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=10
ORCID=

en-aut-name=ZhouWenhao
en-aut-sei=Zhou
en-aut-mei=Wenhao
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=11
ORCID=

en-aut-name=NagasakiJoji
en-aut-sei=Nagasaki
en-aut-mei=Joji
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=12
ORCID=

en-aut-name=KochinVitaly
en-aut-sei=Kochin
en-aut-mei=Vitaly
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=13
ORCID=

en-aut-name=UenoToshihide
en-aut-sei=Ueno
en-aut-mei=Toshihide
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=14
ORCID=

en-aut-name=KojimaShinya
en-aut-sei=Kojima
en-aut-mei=Shinya
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=15
ORCID=

en-aut-name=Honobe-TabuchiAkiko
en-aut-sei=Honobe-Tabuchi
en-aut-mei=Akiko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=16
ORCID=

en-aut-name=KawamuraTatsuyoshi
en-aut-sei=Kawamura
en-aut-mei=Tatsuyoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=17
ORCID=

en-aut-name=OhnumaTakehiro
en-aut-sei=Ohnuma
en-aut-mei=Takehiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=18
ORCID=

en-aut-name=MatsuzawaTakamitsu
en-aut-sei=Matsuzawa
en-aut-mei=Takamitsu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=19
ORCID=

en-aut-name=KawaharaYu
en-aut-sei=Kawahara
en-aut-mei=Yu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=20
ORCID=

en-aut-name=YamashitaKazuo
en-aut-sei=Yamashita
en-aut-mei=Kazuo
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=21
ORCID=

en-aut-name=LinJason
en-aut-sei=Lin
en-aut-mei=Jason
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=22
ORCID=

en-aut-name=KosekiJun
en-aut-sei=Koseki
en-aut-mei=Jun
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=23
ORCID=

en-aut-name=NishikawaHiroyoshi
en-aut-sei=Nishikawa
en-aut-mei=Hiroyoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=24
ORCID=

en-aut-name=ArakiMotoo
en-aut-sei=Araki
en-aut-mei=Motoo
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=25
ORCID=

en-aut-name=KatoNaoya
en-aut-sei=Kato
en-aut-mei=Naoya
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=26
ORCID=

en-aut-name=ShimamuraTeppei
en-aut-sei=Shimamura
en-aut-mei=Teppei
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=27
ORCID=

en-aut-name=MorishitaShinichi
en-aut-sei=Morishita
en-aut-mei=Shinichi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=28
ORCID=

en-aut-name=SuzukiYutaka
en-aut-sei=Suzuki
en-aut-mei=Yutaka
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=29
ORCID=

en-aut-name=ManoHiroyuki
en-aut-sei=Mano
en-aut-mei=Hiroyuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=30
ORCID=

en-aut-name=TorigoeToshihiko
en-aut-sei=Torigoe
en-aut-mei=Toshihiko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=31
ORCID=

en-aut-name=KanasekiTakayuki
en-aut-sei=Kanaseki
en-aut-mei=Takayuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=32
ORCID=

en-aut-name=KawazuMasahito
en-aut-sei=Kawazu
en-aut-mei=Masahito
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=33
ORCID=

en-aut-name=TogashiYosuke
en-aut-sei=Togashi
en-aut-mei=Yosuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=34
ORCID=

affil-num=1
en-affil=Department of Tumor Microenvironment, Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=2
en-affil=Department of Tumor Microenvironment, Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=3
en-affil=Division of Cancer Immunology, Graduate School of Medical and Dental Sciences, Niigata University
kn-affil=

affil-num=4
en-affil=Department of Tumor Microenvironment, Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=5
en-affil=Division of Cell Therapy, Chiba Cancer Center Research Institute
kn-affil=

affil-num=6
en-affil=Department of Tumor Microenvironment, Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=7
en-affil=Department of Tumor Microenvironment, Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=8
en-affil=Department of Computational Biology and Medical Sciences, The University of Tokyo
kn-affil=

affil-num=9
en-affil=Department of Computational Biology and Medical Sciences, The University of Tokyo
kn-affil=

affil-num=10
en-affil=Department of Dermatology, Chiba University Graduate School of Medicine
kn-affil=

affil-num=11
en-affil=Department of Tumor Microenvironment, Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=12
en-affil=Department of Tumor Microenvironment, Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=13
en-affil=Department of Immunology, Nagoya University Graduate School of Medicine
kn-affil=

affil-num=14
en-affil=Division of Cellular Signaling, National Cancer Center Research Institute
kn-affil=

affil-num=15
en-affil=Division of Cellular Signaling, National Cancer Center Research Institute
kn-affil=

affil-num=16
en-affil=Department of Dermatology, University of Yamanashi
kn-affil=

affil-num=17
en-affil=Department of Dermatology, University of Yamanashi
kn-affil=

affil-num=18
en-affil=Department of Dermatology, Kumamoto Kenhoku Hospital
kn-affil=

affil-num=19
en-affil=Department of Dermatology, Chiba University Graduate School of Medicine
kn-affil=

affil-num=20
en-affil=Department of Dermatology, Chiba University Graduate School of Medicine
kn-affil=

affil-num=21
en-affil=KOTAI Biotechnologies, Inc
kn-affil=

affil-num=22
en-affil=Division of Cell Therapy, Chiba Cancer Center Research Institute
kn-affil=

affil-num=23
en-affil=Division of Systems Biology, Nagoya University Graduate School of Medicine
kn-affil=

affil-num=24
en-affil=Department of Immunology, Nagoya University Graduate School of Medicine
kn-affil=

affil-num=25
en-affil=Department of Urology, Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=26
en-affil=Department of Gastroenterology, Graduate School of Medicine, Chiba University
kn-affil=

affil-num=27
en-affil=Division of Systems Biology, Nagoya University Graduate School of Medicine
kn-affil=

affil-num=28
en-affil=Department of Computational Biology and Medical Sciences, The University of Tokyo
kn-affil=

affil-num=29
en-affil=Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo
kn-affil=

affil-num=30
en-affil=Division of Cellular Signaling, National Cancer Center Research Institute
kn-affil=

affil-num=31
en-affil=
kn-affil=

affil-num=32
en-affil=Division of Cancer Immunology, Graduate School of Medical and Dental Sciences, Niigata University
kn-affil=

affil-num=33
en-affil=Division of Cell Therapy, Chiba Cancer Center Research Institute
kn-affil=

affil-num=34
en-affil=Department of Tumor Microenvironment, Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences
kn-affil=
en-keyword=cancer immunology
kn-keyword=cancer immunology
en-keyword=neoantigen
kn-keyword=neoantigen
en-keyword=long-read RNA sequencing
kn-keyword=long-read RNA sequencing
en-keyword=HLA ligandome
kn-keyword=HLA ligandome
en-keyword=single-cell RNA sequencing
kn-keyword=single-cell RNA sequencing
en-keyword=single-cell TCR sequencing
kn-keyword=single-cell TCR sequencing
en-keyword=exhausted T cell
kn-keyword=exhausted T cell
END

start-ver=1.4
cd-journal=joma
no-vol=8
cd-vols=
no-issue=1
article-no=
start-page=1773
end-page=
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2025
dt-pub=20251216
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Single-cell and spatial transcriptomic characterization of pulmonary pleomorphic carcinoma
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Pulmonary pleomorphic carcinoma (PPC) is a rare subtype of lung cancer that comprises both epithelial and sarcomatoid components. The molecular basis of PPC, including the cellular dynamics of its components, remains largely unknown. To elucidate potential therapeutic targets for PPC, we perform a multi-omics analysis incorporating digital spatial profiling and single-cell RNA sequencing (scRNA-seq). PPC exhibits diverse driver gene alterations, including MET exon 14 skipping mutation (METex14) and ALK fusion. In spatial transcriptomics, MET gene and protein are overexpressed exclusively within the epithelial component and not in the sarcomatoid component, even in patients harboring METex14. Epithelial-mesenchymal transition (EMT)-related transcriptional changes, along with extracellular matrix (ECM) remodeling between the epithelial and sarcomatoid components, are observed. scRNA-seq identifies cell populations within the epithelial component that contribute to the malignant transformation and differentiation of the sarcomatoid component. They are characterized by an intermediate EMT state with ECM remodeling signature, suggesting their potential as novel therapeutic targets for PPC.
en-copyright=
kn-copyright=

en-aut-name=MatsuokaAtsushi
en-aut-sei=Matsuoka
en-aut-mei=Atsushi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=ShienKazuhiko
en-aut-sei=Shien
en-aut-mei=Kazuhiko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=TomidaShuta
en-aut-sei=Tomida
en-aut-mei=Shuta
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=OhkiMasayoshi
en-aut-sei=Ohki
en-aut-mei=Masayoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=HisamatsuKazuya
en-aut-sei=Hisamatsu
en-aut-mei=Kazuya
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=FujiwaraRyota
en-aut-sei=Fujiwara
en-aut-mei=Ryota
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=IshimuraKosei
en-aut-sei=Ishimura
en-aut-mei=Kosei
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=FujiiRyunosuke
en-aut-sei=Fujii
en-aut-mei=Ryunosuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=HigashiharaTomoaki
en-aut-sei=Higashihara
en-aut-mei=Tomoaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

en-aut-name=HayashiNaohiro
en-aut-sei=Hayashi
en-aut-mei=Naohiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=10
ORCID=

en-aut-name=OkadaKazuhiro
en-aut-sei=Okada
en-aut-mei=Kazuhiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=11
ORCID=

en-aut-name=YoshichikaRyo
en-aut-sei=Yoshichika
en-aut-mei=Ryo
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=12
ORCID=

en-aut-name=MukoharaFumiaki
en-aut-sei=Mukohara
en-aut-mei=Fumiaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=13
ORCID=

en-aut-name=YoshikawaMao
en-aut-sei=Yoshikawa
en-aut-mei=Mao
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=14
ORCID=

en-aut-name=FukumotoYuma
en-aut-sei=Fukumoto
en-aut-mei=Yuma
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=15
ORCID=

en-aut-name=SuzawaKen
en-aut-sei=Suzawa
en-aut-mei=Ken
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=16
ORCID=

en-aut-name=TomiokaYasuaki
en-aut-sei=Tomioka
en-aut-mei=Yasuaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=17
ORCID=

en-aut-name=TanakaShin
en-aut-sei=Tanaka
en-aut-mei=Shin
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=18
ORCID=

en-aut-name=MiyoshiKentaroh
en-aut-sei=Miyoshi
en-aut-mei=Kentaroh
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=19
ORCID=

en-aut-name=OkazakiMikio
en-aut-sei=Okazaki
en-aut-mei=Mikio
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=20
ORCID=

en-aut-name=SugimotoSeiichiro
en-aut-sei=Sugimoto
en-aut-mei=Seiichiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=21
ORCID=

en-aut-name=OtaniYusuke
en-aut-sei=Otani
en-aut-mei=Yusuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=22
ORCID=

en-aut-name=TanakaAtsushi
en-aut-sei=Tanaka
en-aut-mei=Atsushi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=23
ORCID=

en-aut-name=InoueHirofumi
en-aut-sei=Inoue
en-aut-mei=Hirofumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=24
ORCID=

en-aut-name=TogashiYosuke
en-aut-sei=Togashi
en-aut-mei=Yosuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=25
ORCID=

en-aut-name=YamamotoHidetaka
en-aut-sei=Yamamoto
en-aut-mei=Hidetaka
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=26
ORCID=

en-aut-name=EnnishiDaisuke
en-aut-sei=Ennishi
en-aut-mei=Daisuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=27
ORCID=

en-aut-name=ToyookaShinichi
en-aut-sei=Toyooka
en-aut-mei=Shinichi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=28
ORCID=

affil-num=1
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=2
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=3
en-affil=
kn-affil=

affil-num=4
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=5
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=6
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=7
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=8
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=9
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=10
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=11
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=12
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=13
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=14
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=15
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=16
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=17
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=18
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=19
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=20
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=21
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=22
en-affil=Department of Pathology, Beth Israel Deaconess Medical Center
kn-affil=

affil-num=23
en-affil=Department of Pathology, Beth Israel Deaconess Medical Center
kn-affil=

affil-num=24
en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital
kn-affil=

affil-num=25
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=26
en-affil=Department of Pathology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=27
en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital
kn-affil=

affil-num=28
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=
END

start-ver=1.4
cd-journal=joma
no-vol=64
cd-vols=
no-issue=23
article-no=
start-page=3413
end-page=3418
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2025
dt-pub=20251201
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=A Prompt Diagnosis of Ascites and Dramatic Effect of Alectinib for Advanced Lung Adenocarcinoma Harboring EML4-ALK Fusion
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=A 75-year-old never-smoker woman presented with dyspnea and loss of appetite. A mass was identified in the left upper lobe of the lung, and the patient was referred to our hospital. Despite the diagnosis of lung adenocarcinoma via bronchoscopy, anaplastic lymphoma kinase (ALK) immunostaining was negative. Rapid weight gain and abdominal distension caused by ascites prompted fluid testing using the AmoyDx® Pan Lung Cancer PCR Panel. EML4-ALK fusion was confirmed, and alectinib therapy was initiated immediately. The tumor size had decreased significantly, and the patient was discharged on day 34. This case highlights the necessity of multiplex genetic testing even when ALK immunostaining is negative.
en-copyright=
kn-copyright=

en-aut-name=BabaTakahiro
en-aut-sei=Baba
en-aut-mei=Takahiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=InoueHirofumi
en-aut-sei=Inoue
en-aut-mei=Hirofumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=MatsuokaHiromi
en-aut-sei=Matsuoka
en-aut-mei=Hiromi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=KyakunoMio
en-aut-sei=Kyakuno
en-aut-mei=Mio
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=YoshinagaYusuke
en-aut-sei=Yoshinaga
en-aut-mei=Yusuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=TakeguchiTetsuya
en-aut-sei=Takeguchi
en-aut-mei=Tetsuya
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=FujiwaraMiho
en-aut-sei=Fujiwara
en-aut-mei=Miho
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=YamadaKotaro
en-aut-sei=Yamada
en-aut-mei=Kotaro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=NakamuraEri
en-aut-sei=Nakamura
en-aut-mei=Eri
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

en-aut-name=MoritaAyako
en-aut-sei=Morita
en-aut-mei=Ayako
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=10
ORCID=

en-aut-name=HaraNaofumi
en-aut-sei=Hara
en-aut-mei=Naofumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=11
ORCID=

en-aut-name=NinomiyaKiichiro
en-aut-sei=Ninomiya
en-aut-mei=Kiichiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=12
ORCID=

en-aut-name=HigoHisao
en-aut-sei=Higo
en-aut-mei=Hisao
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=13
ORCID=

en-aut-name=FujiiMasanori
en-aut-sei=Fujii
en-aut-mei=Masanori
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=14
ORCID=

en-aut-name=IchiharaEiki
en-aut-sei=Ichihara
en-aut-mei=Eiki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=15
ORCID=

en-aut-name=RaiKammei
en-aut-sei=Rai
en-aut-mei=Kammei
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=16
ORCID=

en-aut-name=OhashiKadoaki
en-aut-sei=Ohashi
en-aut-mei=Kadoaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=17
ORCID=

en-aut-name=HottaKatsuyuki
en-aut-sei=Hotta
en-aut-mei=Katsuyuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=18
ORCID=

en-aut-name=TabataMasahiro
en-aut-sei=Tabata
en-aut-mei=Masahiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=19
ORCID=

en-aut-name=MaedaYoshinobu
en-aut-sei=Maeda
en-aut-mei=Yoshinobu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=20
ORCID=

en-aut-name=TogashiYosuke
en-aut-sei=Togashi
en-aut-mei=Yosuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=21
ORCID=

en-aut-name=MakimotoGo
en-aut-sei=Makimoto
en-aut-mei=Go
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=22
ORCID=

affil-num=1
en-affil=Department of Respiratory Medicine, Okayama University Hospital
kn-affil=

affil-num=2
en-affil=Department of Medical Support, Okayama University Hospital
kn-affil=

affil-num=3
en-affil=Department of Medical Support, Okayama University Hospital
kn-affil=

affil-num=4
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine
kn-affil=

affil-num=5
en-affil=Department of Respiratory Medicine, Okayama University Hospital
kn-affil=

affil-num=6
en-affil=Department of Respiratory Medicine, Okayama University Hospital
kn-affil=

affil-num=7
en-affil=Department of Respiratory Medicine, Okayama University Hospital
kn-affil=

affil-num=8
en-affil=Department of Respiratory Medicine, Okayama University Hospital
kn-affil=

affil-num=9
en-affil=Department of Respiratory Medicine, Okayama University Hospital
kn-affil=

affil-num=10
en-affil=Department of Respiratory Medicine, Okayama University Hospital
kn-affil=

affil-num=11
en-affil=Department of Respiratory Medicine, Okayama University Hospital
kn-affil=

affil-num=12
en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital
kn-affil=

affil-num=13
en-affil=Department of Respiratory Medicine, Okayama University Hospital
kn-affil=

affil-num=14
en-affil=Department of Geriatric Medicine, Okayama University Hospital
kn-affil=

affil-num=15
en-affil=Center for Clinical Oncology, Okayama University Hospital
kn-affil=

affil-num=16
en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital
kn-affil=

affil-num=17
en-affil=Department of Respiratory Medicine, Okayama University Hospital
kn-affil=

affil-num=18
en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital
kn-affil=

affil-num=19
en-affil=Center for Clinical Oncology, Okayama University Hospital
kn-affil=

affil-num=20
en-affil=Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
kn-affil=

affil-num=21
en-affil=Department of Respiratory Medicine, Okayama University Hospital
kn-affil=

affil-num=22
en-affil=Department of Respiratory Medicine, Okayama University Hospital
kn-affil=
en-keyword=lung adenocarcinoma
kn-keyword=lung adenocarcinoma
en-keyword=EML4-ALK
kn-keyword=EML4-ALK
en-keyword=AmoyDxⓇ Pan Lung Cancer PCR Panel
kn-keyword=AmoyDxⓇ Pan Lung Cancer PCR Panel
en-keyword=alectinib
kn-keyword=alectinib
END

start-ver=1.4
cd-journal=joma
no-vol=
cd-vols=
no-issue=
article-no=
start-page=
end-page=
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2025
dt-pub=20251104
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Optogenetic Cancer Therapy Using the Light-Driven Outward Proton Pump Rhodopsin Archaerhodopsin-3 (AR3)
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Medicines used for cancer treatment often cause serious side effects by damaging normal cells due to nonspecific diffusion. To address this issue, we previously developed an optical method to induce apoptotic cell death via intracellular pH alkalinization using the outward proton pump rhodopsin, Archaerhodopsin-3 (AR3) in various noncancer model cells in vitro and in vivo. In this study, we applied this method to cancer cells and tumors to evaluate its potential as an anticancer therapeutic strategy. First, we confirmed that AR3-expressing murine cancer cell lines (MC38, B16F10) showed apoptotic cell death upon green light irradiation, as indicated by increased levels of cell death and apoptosis-related markers. Next, we established stable AR3-expressing MC38 and B16F10 cells by using viral vectors. When these AR3-expressing cells were subcutaneously transplanted into C57BL/6 mice, the resulting tumors initially grew at a rate comparable to that of control tumors lacking AR3 expression or light stimulation. However, upon green light irradiation, AR3-expressing tumors exhibited either a marked reduction in size or significantly suppressed growth, accompanied by the induction of apoptosis signals and decreased proliferation signals. These results demonstrate that AR3-mediated cell death has potent antitumor effects both in vitro and in vivo. This optical method thus holds promise as a novel cancer therapy with potentially reduced side effects.
en-copyright=
kn-copyright=

en-aut-name=NakaoShin
en-aut-sei=Nakao
en-aut-mei=Shin
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=KojimaKeiichi
en-aut-sei=Kojima
en-aut-mei=Keiichi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=SatoKeita
en-aut-sei=Sato
en-aut-mei=Keita
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=KemmotsuNaoya
en-aut-sei=Kemmotsu
en-aut-mei=Naoya
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=OhuchiHideyo
en-aut-sei=Ohuchi
en-aut-mei=Hideyo
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=TogashiYosuke
en-aut-sei=Togashi
en-aut-mei=Yosuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=SudoYuki
en-aut-sei=Sudo
en-aut-mei=Yuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

affil-num=1
en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=2
en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=3
en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=4
en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=5
en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=6
en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=7
en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=
END

start-ver=1.4
cd-journal=joma
no-vol=638
cd-vols=
no-issue=8049
article-no=
start-page=225
end-page=236
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2025
dt-pub=20250122
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Immune evasion through mitochondrial transfer in the tumour microenvironment
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Cancer cells in the tumour microenvironment use various mechanisms to evade the immune system, particularly T cell attack1. For example, metabolic reprogramming in the tumour microenvironment and mitochondrial dysfunction in tumour-infiltrating lymphocytes (TILs) impair antitumour immune responses2,3,4. However, detailed mechanisms of such processes remain unclear. Here we analyse clinical specimens and identify mitochondrial DNA (mtDNA) mutations in TILs that are shared with cancer cells. Moreover, mitochondria with mtDNA mutations from cancer cells are able to transfer to TILs. Typically, mitochondria in TILs readily undergo mitophagy through reactive oxygen species. However, mitochondria transferred from cancer cells do not undergo mitophagy, which we find is due to mitophagy-inhibitory molecules. These molecules attach to mitochondria and together are transferred to TILs, which results in homoplasmic replacement. T cells that acquire mtDNA mutations from cancer cells exhibit metabolic abnormalities and senescence, with defects in effector functions and memory formation. This in turn leads to impaired antitumour immunity both in vitro and in vivo. Accordingly, the presence of an mtDNA mutation in tumour tissue is a poor prognostic factor for immune checkpoint inhibitors in patients with melanoma or non-small-cell lung cancer. These findings reveal a previously unknown mechanism of cancer immune evasion through mitochondrial transfer and can contribute to the development of future cancer immunotherapies.
en-copyright=
kn-copyright=

en-aut-name=IkedaHideki
en-aut-sei=Ikeda
en-aut-mei=Hideki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=KawaseKatsushige
en-aut-sei=Kawase
en-aut-mei=Katsushige
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=NishiTatsuya
en-aut-sei=Nishi
en-aut-mei=Tatsuya
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=WatanabeTomofumi
en-aut-sei=Watanabe
en-aut-mei=Tomofumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=TakenagaKeizo
en-aut-sei=Takenaga
en-aut-mei=Keizo
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=InozumeTakashi
en-aut-sei=Inozume
en-aut-mei=Takashi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=IshinoTakamasa
en-aut-sei=Ishino
en-aut-mei=Takamasa
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=AkiSho
en-aut-sei=Aki
en-aut-mei=Sho
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=LinJason
en-aut-sei=Lin
en-aut-mei=Jason
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

en-aut-name=KawashimaShusuke
en-aut-sei=Kawashima
en-aut-mei=Shusuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=10
ORCID=

en-aut-name=NagasakiJoji
en-aut-sei=Nagasaki
en-aut-mei=Joji
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=11
ORCID=

en-aut-name=UedaYouki
en-aut-sei=Ueda
en-aut-mei=Youki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=12
ORCID=

en-aut-name=SuzukiShinichiro
en-aut-sei=Suzuki
en-aut-mei=Shinichiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=13
ORCID=

en-aut-name=MakinoshimaHideki
en-aut-sei=Makinoshima
en-aut-mei=Hideki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=14
ORCID=

en-aut-name=ItamiMakiko
en-aut-sei=Itami
en-aut-mei=Makiko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=15
ORCID=

en-aut-name=NakamuraYuki
en-aut-sei=Nakamura
en-aut-mei=Yuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=16
ORCID=

en-aut-name=TatsumiYasutoshi
en-aut-sei=Tatsumi
en-aut-mei=Yasutoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=17
ORCID=

en-aut-name=SuenagaYusuke
en-aut-sei=Suenaga
en-aut-mei=Yusuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=18
ORCID=

en-aut-name=MorinagaTakao
en-aut-sei=Morinaga
en-aut-mei=Takao
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=19
ORCID=

en-aut-name=Honobe-TabuchiAkiko
en-aut-sei=Honobe-Tabuchi
en-aut-mei=Akiko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=20
ORCID=

en-aut-name=OhnumaTakehiro
en-aut-sei=Ohnuma
en-aut-mei=Takehiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=21
ORCID=

en-aut-name=KawamuraTatsuyoshi
en-aut-sei=Kawamura
en-aut-mei=Tatsuyoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=22
ORCID=

en-aut-name=UmedaYoshiyasu
en-aut-sei=Umeda
en-aut-mei=Yoshiyasu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=23
ORCID=

en-aut-name=NakamuraYasuhiro
en-aut-sei=Nakamura
en-aut-mei=Yasuhiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=24
ORCID=

en-aut-name=KiniwaYukiko
en-aut-sei=Kiniwa
en-aut-mei=Yukiko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=25
ORCID=

en-aut-name=IchiharaEiki
en-aut-sei=Ichihara
en-aut-mei=Eiki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=26
ORCID=

en-aut-name=HayashiHidetoshi
en-aut-sei=Hayashi
en-aut-mei=Hidetoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=27
ORCID=

en-aut-name=IkedaJun-ichiro
en-aut-sei=Ikeda
en-aut-mei=Jun-ichiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=28
ORCID=

en-aut-name=HanazawaToyoyuki
en-aut-sei=Hanazawa
en-aut-mei=Toyoyuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=29
ORCID=

en-aut-name=ToyookaShinichi
en-aut-sei=Toyooka
en-aut-mei=Shinichi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=30
ORCID=

en-aut-name=ManoHiroyuki
en-aut-sei=Mano
en-aut-mei=Hiroyuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=31
ORCID=

en-aut-name=SuzukiTakuji
en-aut-sei=Suzuki
en-aut-mei=Takuji
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=32
ORCID=

en-aut-name=OsawaTsuyoshi
en-aut-sei=Osawa
en-aut-mei=Tsuyoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=33
ORCID=

en-aut-name=KawazuMasahito
en-aut-sei=Kawazu
en-aut-mei=Masahito
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=34
ORCID=

en-aut-name=TogashiYosuke
en-aut-sei=Togashi
en-aut-mei=Yosuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=35
ORCID=

affil-num=1
en-affil=Division of Cell Therapy, Chiba Cancer Center Research Institute
kn-affil=

affil-num=2
en-affil=Division of Cell Therapy, Chiba Cancer Center Research Institute
kn-affil=

affil-num=3
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=4
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=5
en-affil=Division of Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute
kn-affil=

affil-num=6
en-affil=Division of Cell Therapy, Chiba Cancer Center Research Institute
kn-affil=

affil-num=7
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=8
en-affil=Division of Nutriomics and Oncology, RCAST, The University of Tokyo
kn-affil=

affil-num=9
en-affil=Division of Cell Therapy, Chiba Cancer Center Research Institute
kn-affil=

affil-num=10
en-affil=Division of Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan Department of Dermatology, Graduate School of Medicine, Chiba University
kn-affil=

affil-num=11
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=12
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=13
en-affil=Department of Medical Oncology, Kindai University Faculty of Medicine
kn-affil=

affil-num=14
en-affil=Tsuruoka Metabolomics Laboratory, National Cancer Center
kn-affil=

affil-num=15
en-affil=Department of Surgical Pathology, Chiba Cancer Center
kn-affil=

affil-num=16
en-affil=Division of Cell Therapy, Chiba Cancer Center Research Institute
kn-affil=

affil-num=17
en-affil=Division of Cell Therapy, Chiba Cancer Center Research Institute
kn-affil=

affil-num=18
en-affil=Laboratory of Evolutionary Oncology, Chiba Cancer Center Research Institute
kn-affil=

affil-num=19
en-affil=Division of Cell Therapy, Chiba Cancer Center Research Institute
kn-affil=

affil-num=20
en-affil=Department of Dermatology, Faculty of Medicine, University of Yamanashi
kn-affil=

affil-num=21
en-affil=Department of Dermatology, Faculty of Medicine, University of Yamanashi
kn-affil=

affil-num=22
en-affil=Department of Dermatology, Faculty of Medicine, University of Yamanashi
kn-affil=

affil-num=23
en-affil=Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center
kn-affil=

affil-num=24
en-affil=Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center
kn-affil=

affil-num=25
en-affil=Department of Dermatology, Shinshu University School of Medicine
kn-affil=

affil-num=26
en-affil=Department of Allergy and Respiratory Medicine, Okayama University Hospital
kn-affil=

affil-num=27
en-affil=Department of Medical Oncology, Kindai University Faculty of Medicine
kn-affil=

affil-num=28
en-affil=Department of Diagnostic Pathology, Graduate School of Medicine, Chiba University
kn-affil=

affil-num=29
en-affil=Department of Otorhinolaryngology/Head and Neck Surgery, Chiba University Graduate School of Medicine
kn-affil=

affil-num=30
en-affil=Department of General Thoracic Surgery and Endocrinological Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=31
en-affil=Division of Cellular Signalling, National Cancer Center Research Institute
kn-affil=

affil-num=32
en-affil=Department of Respirology, Graduate School of Medicine, Chiba University
kn-affil=

affil-num=33
en-affil=Division of Nutriomics and Oncology, RCAST, The University of Tokyo
kn-affil=

affil-num=34
en-affil=Division of Cell Therapy, Chiba Cancer Center Research Institute
kn-affil=

affil-num=35
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=
END

start-ver=1.4
cd-journal=joma
no-vol=116
cd-vols=
no-issue=5
article-no=
start-page=1214
end-page=1226
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2025
dt-pub=20250227
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=High Antigenicity for Treg Cells Confers Resistance to PD-1 Blockade Therapy via High PD-1 Expression in Treg Cells
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Regulatory T (Treg) cells have an immunosuppressive function, and programmed death-1 (PD-1)-expressing Treg cells reportedly induce resistance to PD-1 blockade therapies through their reactivation. However, the effects of antigenicity on PD-1 expression in Treg cells and the resistance to PD-1 blockade therapy remain unclear. Here, we show that Treg cells gain high PD-1 expression through an antigen with high antigenicity. Additionally, tumors with high antigenicity for Treg cells were resistant to PD-1 blockade in vivo due to PD-1+ Treg-cell infiltration. Because such PD-1+ Treg cells have high cytotoxic T lymphocyte antigen (CTLA)-4 expression, resistance could be overcome by combination with an anti-CTLA-4 monoclonal antibody (mAb). Patients who responded to combination therapy with anti-PD-1 and anti-CTLA-4 mAbs sequentially after primary resistance to PD-1 blockade monotherapy showed high Treg cell infiltration. We propose that the high antigenicity of Treg cells confers resistance to PD-1 blockade therapy via high PD-1 expression in Treg cells, which can be overcome by combination therapy with an anti-CTLA-4 mAb.
en-copyright=
kn-copyright=

en-aut-name=MatsuuraHiroaki
en-aut-sei=Matsuura
en-aut-mei=Hiroaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=IshinoTakamasa
en-aut-sei=Ishino
en-aut-mei=Takamasa
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=NinomiyaToshifumi
en-aut-sei=Ninomiya
en-aut-mei=Toshifumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=NinomiyaKiichiro
en-aut-sei=Ninomiya
en-aut-mei=Kiichiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=TachibanaKota
en-aut-sei=Tachibana
en-aut-mei=Kota
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=Honobe-TabuchiAkiko
en-aut-sei=Honobe-Tabuchi
en-aut-mei=Akiko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=MutoYoshinori
en-aut-sei=Muto
en-aut-mei=Yoshinori
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=InozumeTakashi
en-aut-sei=Inozume
en-aut-mei=Takashi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=UedaYouki
en-aut-sei=Ueda
en-aut-mei=Youki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

en-aut-name=OhashiKadoaki
en-aut-sei=Ohashi
en-aut-mei=Kadoaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=10
ORCID=

en-aut-name=MaedaYoshinobu
en-aut-sei=Maeda
en-aut-mei=Yoshinobu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=11
ORCID=

en-aut-name=NagasakiJoji
en-aut-sei=Nagasaki
en-aut-mei=Joji
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=12
ORCID=

en-aut-name=TogashiYosuke
en-aut-sei=Togashi
en-aut-mei=Yosuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=13
ORCID=

affil-num=1
en-affil=Department of Tumor Microenvironment, Okayama University
kn-affil=

affil-num=2
en-affil=Department of Tumor Microenvironment, Okayama University
kn-affil=

affil-num=3
en-affil=Department of Tumor Microenvironment, Okayama University
kn-affil=

affil-num=4
en-affil=Department of Hematology, Oncology and Respiratory Medicine,Okayama University
kn-affil=

affil-num=5
en-affil=Department of Dermatology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=6
en-affil=Department of Dermatology, University of Yamanashi
kn-affil=

affil-num=7
en-affil=Department of Dermatology, University of Yamanashi
kn-affil=

affil-num=8
en-affil=Department of Dermatology, University of Yamanashi
kn-affil=

affil-num=9
en-affil=Department of Tumor Microenvironment, Okayama University
kn-affil=

affil-num=10
en-affil=Department of Hematology, Oncology and Respiratory Medicine,Okayama University
kn-affil=

affil-num=11
en-affil=Department of Hematology, Oncology and Respiratory Medicine,Okayama University
kn-affil=

affil-num=12
en-affil=Department of Tumor Microenvironment, Okayama University
kn-affil=

affil-num=13
en-affil=Department of Tumor Microenvironment, Okayama University
kn-affil=
en-keyword=antigenicity
kn-keyword=antigenicity
en-keyword=cancer immunotherapy
kn-keyword=cancer immunotherapy
en-keyword=CTLA-4
kn-keyword=CTLA-4
en-keyword=PD-1
kn-keyword=PD-1
en-keyword=regulatory T cell
kn-keyword=regulatory T cell
END

start-ver=1.4
cd-journal=joma
no-vol=121
cd-vols=
no-issue=35
article-no=
start-page=e2320189121
end-page=
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2024
dt-pub=20240821
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Somatic mutations in tumor-infiltrating lymphocytes impact on antitumor immunity
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Immune checkpoint inhibitors (ICIs) exert clinical efficacy against various types of cancers by reinvigorating exhausted CD8+ T cells that can expand and directly attack cancer cells (cancer-specific T cells) among tumor-infiltrating lymphocytes (TILs). Although some reports have identified somatic mutations in TILs, their effect on antitumor immunity remains unclear. In this study, we successfully established 18 cancer-specific T cell clones, which have an exhaustion phenotype, from the TILs of four patients with melanoma. We conducted whole-genome sequencing for these T cell clones and identified various somatic mutations in them with high clonality. Among the somatic mutations, an SH2D2A loss-of-function frameshift mutation and TNFAIP3 deletion could activate T cell effector functions in vitro. Furthermore, we generated CD8+ T cell–specific Tnfaip3 knockout mice and showed that Tnfaip3 function loss in CD8+ T cell increased antitumor immunity, leading to remarkable response to PD-1 blockade in vivo. In addition, we analyzed bulk CD3+ T cells from TILs in additional 12 patients and identified an SH2D2A mutation in one patient through amplicon sequencing. These findings suggest that somatic mutations in TILs can affect antitumor immunity and suggest unique biomarkers and therapeutic targets.
en-copyright=
kn-copyright=

en-aut-name=MukoharaFumiaki
en-aut-sei=Mukohara
en-aut-mei=Fumiaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=IwataKazuma
en-aut-sei=Iwata
en-aut-mei=Kazuma
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=IshinoTakamasa
en-aut-sei=Ishino
en-aut-mei=Takamasa
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=InozumeTakashi
en-aut-sei=Inozume
en-aut-mei=Takashi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=NagasakiJoji
en-aut-sei=Nagasaki
en-aut-mei=Joji
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=UedaYouki
en-aut-sei=Ueda
en-aut-mei=Youki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=SuzawaKen
en-aut-sei=Suzawa
en-aut-mei=Ken
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=UenoToshihide
en-aut-sei=Ueno
en-aut-mei=Toshihide
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=IkedaHideki
en-aut-sei=Ikeda
en-aut-mei=Hideki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

en-aut-name=KawaseKatsushige
en-aut-sei=Kawase
en-aut-mei=Katsushige
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=10
ORCID=

en-aut-name=SaekiYuka
en-aut-sei=Saeki
en-aut-mei=Yuka
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=11
ORCID=

en-aut-name=KawashimaShusuke
en-aut-sei=Kawashima
en-aut-mei=Shusuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=12
ORCID=

en-aut-name=YamashitaKazuo
en-aut-sei=Yamashita
en-aut-mei=Kazuo
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=13
ORCID=

en-aut-name=KawaharaYu
en-aut-sei=Kawahara
en-aut-mei=Yu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=14
ORCID=

en-aut-name=NakamuraYasuhiro
en-aut-sei=Nakamura
en-aut-mei=Yasuhiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=15
ORCID=

en-aut-name=Honobe-TabuchiAkiko
en-aut-sei=Honobe-Tabuchi
en-aut-mei=Akiko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=16
ORCID=

en-aut-name=WatanabeHiroko
en-aut-sei=Watanabe
en-aut-mei=Hiroko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=17
ORCID=

en-aut-name=DansakoHiromichi
en-aut-sei=Dansako
en-aut-mei=Hiromichi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=18
ORCID=

en-aut-name=KawamuraTatsuyoshi
en-aut-sei=Kawamura
en-aut-mei=Tatsuyoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=19
ORCID=

en-aut-name=SuzukiYutaka
en-aut-sei=Suzuki
en-aut-mei=Yutaka
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=20
ORCID=

en-aut-name=HondaHiroaki
en-aut-sei=Honda
en-aut-mei=Hiroaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=21
ORCID=

en-aut-name=ManoHiroyuki
en-aut-sei=Mano
en-aut-mei=Hiroyuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=22
ORCID=

en-aut-name=ToyookaShinichi
en-aut-sei=Toyooka
en-aut-mei=Shinichi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=23
ORCID=

en-aut-name=KawazuMasahito
en-aut-sei=Kawazu
en-aut-mei=Masahito
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=24
ORCID=

en-aut-name=TogashiYosuke
en-aut-sei=Togashi
en-aut-mei=Yosuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=25
ORCID=

affil-num=1
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=2
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=3
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=4
en-affil=Department of Dermatology, Chiba University Graduate School of Medicine
kn-affil=

affil-num=5
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=6
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=7
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama University
kn-affil=

affil-num=8
en-affil=Division of Cellular Signaling, National Cancer Center Research Institute
kn-affil=

affil-num=9
en-affil=Division of Cell Therapy, Chiba Cancer Research Institute
kn-affil=

affil-num=10
en-affil=Division of Cell Therapy, Chiba Cancer Research Institute
kn-affil=

affil-num=11
en-affil=Department of Dermatology, Chiba University Graduate School of Medicine
kn-affil=

affil-num=12
en-affil=Department of Dermatology, Chiba University Graduate School of Medicine
kn-affil=

affil-num=13
en-affil=KOTAI Biotechnologies, Inc.
kn-affil=

affil-num=14
en-affil=Department of Dermatology, Chiba University Graduate School of Medicine
kn-affil=

affil-num=15
en-affil=Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center
kn-affil=

affil-num=16
en-affil=Department of Dermatology, University of Yamanashi
kn-affil=

affil-num=17
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=18
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=19
en-affil=Department of Dermatology, University of Yamanashi
kn-affil=

affil-num=20
en-affil=Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa
kn-affil=

affil-num=21
en-affil=Department of Pathology, Tokyo Women's Medical University
kn-affil=

affil-num=22
en-affil=Division of Cellular Signaling, National Cancer Center Research Institute
kn-affil=

affil-num=23
en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama University
kn-affil=

affil-num=24
en-affil=Division of Cell Therapy, Chiba Cancer Research Institute
kn-affil=

affil-num=25
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=
en-keyword=cancer immunology
kn-keyword=cancer immunology
en-keyword=somatic mutation
kn-keyword=somatic mutation
en-keyword=T cell
kn-keyword=T cell
en-keyword=tumor-infiltrating lymphocytes
kn-keyword=tumor-infiltrating lymphocytes
END

start-ver=1.4
cd-journal=joma
no-vol=115
cd-vols=
no-issue=10
article-no=
start-page=3231
end-page=3247
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2024
dt-pub=20240809
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Overcoming immunotherapy resistance and inducing abscopal effects with boron neutron immunotherapy (B-NIT)
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Immune checkpoint inhibitors (ICIs) are effective against many advanced malignancies. However, many patients are nonresponders to immunotherapy, and overcoming this resistance to treatment is important. Boron neutron capture therapy (BNCT) is a local chemoradiation therapy with the combination of boron drugs that accumulate selectively in cancer and the neutron irradiation of the cancer site. Here, we report the first boron neutron immunotherapy (B-NIT), combining BNCT and ICI immunotherapy, which was performed on a radioresistant and immunotherapy-resistant advanced-stage B16F10 melanoma mouse model. The BNCT group showed localized tumor suppression, but the anti-PD-1 antibody immunotherapy group did not show tumor suppression. Only the B-NIT group showed strong tumor growth inhibition at both BNCT-treated and shielded distant sites. Intratumoral CD8+ T-cell infiltration and serum high mobility group box 1 (HMGB1) levels were higher in the B-NIT group. Analysis of CD8(+) T cells in tumor-infiltrating lymphocytes (TILs) showed that CD62L- CD44(+) effector memory T cells and CD69(+) early-activated T cells were predominantly increased in the B-NIT group. Administration of CD8-depleting mAb to the B-NIT group completely suppressed the augmented therapeutic effects. This indicated that B-NIT has a potent immune-induced abscopal effect, directly destroying tumors with BNCT, inducing antigen-spreading effects, and protecting normal tissue. B-NIT, immunotherapy combined with BNCT, is the first treatment to overcome immunotherapy resistance in malignant melanoma. In the future, as its therapeutic efficacy is demonstrated not only in melanoma but also in other immunotherapy-resistant malignancies, B-NIT can become a new treatment candidate for advanced-stage cancers.
en-copyright=
kn-copyright=

en-aut-name=FujimotoTakuya
en-aut-sei=Fujimoto
en-aut-mei=Takuya
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=YamasakiOsamu
en-aut-sei=Yamasaki
en-aut-mei=Osamu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=KanehiraNoriyuki
en-aut-sei=Kanehira
en-aut-mei=Noriyuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=MatsushitaHirokazu
en-aut-sei=Matsushita
en-aut-mei=Hirokazu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=SakuraiYoshinori
en-aut-sei=Sakurai
en-aut-mei=Yoshinori
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=KenmotsuNaoya
en-aut-sei=Kenmotsu
en-aut-mei=Naoya
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=MizutaRyo
en-aut-sei=Mizuta
en-aut-mei=Ryo
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=KondoNatsuko
en-aut-sei=Kondo
en-aut-mei=Natsuko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=TakataTakushi
en-aut-sei=Takata
en-aut-mei=Takushi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

en-aut-name=KitamatsuMizuki
en-aut-sei=Kitamatsu
en-aut-mei=Mizuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=10
ORCID=

en-aut-name=IgawaKazuyo
en-aut-sei=Igawa
en-aut-mei=Kazuyo
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=11
ORCID=

en-aut-name=FujimuraAtsushi
en-aut-sei=Fujimura
en-aut-mei=Atsushi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=12
ORCID=

en-aut-name=OtaniYoshihiro
en-aut-sei=Otani
en-aut-mei=Yoshihiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=13
ORCID=

en-aut-name=ShirakawaMakoto
en-aut-sei=Shirakawa
en-aut-mei=Makoto
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=14
ORCID=

en-aut-name=ShigeyasuKunitoshi
en-aut-sei=Shigeyasu
en-aut-mei=Kunitoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=15
ORCID=

en-aut-name=TeraishiFuminori
en-aut-sei=Teraishi
en-aut-mei=Fuminori
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=16
ORCID=

en-aut-name=TogashiYosuke
en-aut-sei=Togashi
en-aut-mei=Yosuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=17
ORCID=

en-aut-name=SuzukiMinoru
en-aut-sei=Suzuki
en-aut-mei=Minoru
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=18
ORCID=

en-aut-name=FujiwaraToshiyoshi
en-aut-sei=Fujiwara
en-aut-mei=Toshiyoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=19
ORCID=

en-aut-name=MichiueHiroyuki
en-aut-sei=Michiue
en-aut-mei=Hiroyuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=20
ORCID=

affil-num=1
en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
kn-affil=

affil-num=2
en-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
kn-affil=

affil-num=3
en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
kn-affil=

affil-num=4
en-affil=Division of Translational Oncoimmunology, Aichi Cancer Center Research Institute
kn-affil=

affil-num=5
en-affil=Institute for Integrated Radiation and Nuclear Science, Kyoto University
kn-affil=

affil-num=6
en-affil=Department of Tumor Microenvironment, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
kn-affil=

affil-num=7
en-affil=Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
kn-affil=

affil-num=8
en-affil=Institute for Integrated Radiation and Nuclear Science, Kyoto University
kn-affil=

affil-num=9
en-affil=Institute for Integrated Radiation and Nuclear Science, Kyoto University
kn-affil=

affil-num=10
en-affil=Faculty of Science and Engineering, Kindai University
kn-affil=

affil-num=11
en-affil=Neutron Therapy Research Center, Okayama University
kn-affil=

affil-num=12
en-affil=Neutron Therapy Research Center, Okayama University
kn-affil=

affil-num=13
en-affil=Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
kn-affil=

affil-num=14
en-affil=Neutron Therapy Research Center, Okayama University
kn-affil=

affil-num=15
en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
kn-affil=

affil-num=16
en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
kn-affil=

affil-num=17
en-affil=Department of Tumor Microenvironment, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
kn-affil=

affil-num=18
en-affil=Institute for Integrated Radiation and Nuclear Science, Kyoto University
kn-affil=

affil-num=19
en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
kn-affil=

affil-num=20
en-affil=Neutron Therapy Research Center, Okayama University
kn-affil=
en-keyword=abscopal effect
kn-keyword=abscopal effect
en-keyword=advanced melanoma
kn-keyword=advanced melanoma
en-keyword=boron neutron capture therapy
kn-keyword=boron neutron capture therapy
en-keyword=boron-neutron immunotherapy
kn-keyword=boron-neutron immunotherapy
en-keyword=immune combination therapy
kn-keyword=immune combination therapy
END

start-ver=1.4
cd-journal=joma
no-vol=43
cd-vols=
no-issue=2
article-no=
start-page=113797
end-page=
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2024
dt-pub=20240227
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Stem-like progenitor and terminally differentiated TFH-like CD4+ T cell exhaustion in the tumor microenvironment
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Immune checkpoint inhibitors exert clinical efficacy against various types of cancer through reinvigoration of exhausted CD8+ T cells that attack cancer cells directly in the tumor microenvironment (TME). Using single-cell sequencing and mouse models, we show that CXCL13, highly expressed in tumor-infiltrating exhausted CD8+ T cells, induces CD4+ follicular helper T (TFH) cell infiltration, contributing to anti-tumor immunity. Furthermore, a part of the TFH cells in the TME exhibits cytotoxicity and directly attacks major histocompatibility complex-II-expressing tumors. TFH-like cytotoxic CD4+ T cells have high LAG-3/BLIMP1 and low TCF1 expression without self-renewal ability, whereas non-cytotoxic TFH cells express low LAG-3/BLIMP1 and high TCF1 with self-renewal ability, closely resembling the relationship between terminally differentiated and stem-like progenitor exhaustion in CD8+ T cells, respectively. Our findings provide deep insights into TFH-like CD4+ T cell exhaustion with helper progenitor and cytotoxic differentiated functions, mediating anti-tumor immunity orchestrally with CD8+ T cells.
en-copyright=
kn-copyright=

en-aut-name=ZhouWenhao
en-aut-sei=Zhou
en-aut-mei=Wenhao
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=KawashimaShusuke
en-aut-sei=Kawashima
en-aut-mei=Shusuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=IshinoTakamasa
en-aut-sei=Ishino
en-aut-mei=Takamasa
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=KawaseKatsushige
en-aut-sei=Kawase
en-aut-mei=Katsushige
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=UedaYouki
en-aut-sei=Ueda
en-aut-mei=Youki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=YamashitaKazuo
en-aut-sei=Yamashita
en-aut-mei=Kazuo
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=WatanabeTomofumi
en-aut-sei=Watanabe
en-aut-mei=Tomofumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=KawazuMasahito
en-aut-sei=Kawazu
en-aut-mei=Masahito
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=DansakoHiromichi
en-aut-sei=Dansako
en-aut-mei=Hiromichi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

en-aut-name=SuzukiYutaka
en-aut-sei=Suzuki
en-aut-mei=Yutaka
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=10
ORCID=

en-aut-name=NishikawaHiroyoshi
en-aut-sei=Nishikawa
en-aut-mei=Hiroyoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=11
ORCID=

en-aut-name=InozumeTakashi
en-aut-sei=Inozume
en-aut-mei=Takashi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=12
ORCID=

en-aut-name=NagasakiJoji
en-aut-sei=Nagasaki
en-aut-mei=Joji
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=13
ORCID=

en-aut-name=TogashiYosuke
en-aut-sei=Togashi
en-aut-mei=Yosuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=14
ORCID=

affil-num=1
en-affil=Department of Tumor Microenvironment, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=2
en-affil=Department of Dermatology, Chiba University Graduate School of Medicine
kn-affil=

affil-num=3
en-affil=Department of Tumor Microenvironment, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=4
en-affil=Chiba Cancer Center, Research Institute
kn-affil=

affil-num=5
en-affil=Department of Tumor Microenvironment, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=6
en-affil=KOTAI Biotechnologies, Inc. 
kn-affil=

affil-num=7
en-affil=Department of Tumor Microenvironment, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=8
en-affil=Chiba Cancer Center, Research Institute, Division of Cell Therapy
kn-affil=

affil-num=9
en-affil=Department of Tumor Microenvironment, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=10
en-affil=Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo
kn-affil=

affil-num=11
en-affil=Department of Immunology, Nagoya University Graduate School of Medicine
kn-affil=

affil-num=12
en-affil=Department of Dermatology, Chiba University Graduate School of Medicine
kn-affil=

affil-num=13
en-affil=Department of Tumor Microenvironment, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=14
en-affil=Department of Tumor Microenvironment, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=
en-keyword=cancer immunology
kn-keyword=cancer immunology
en-keyword=follicular helper T cell
kn-keyword=follicular helper T cell
en-keyword=cytotoxic CD4+ T cell
kn-keyword=cytotoxic CD4+ T cell
en-keyword=CXCL13
kn-keyword=CXCL13
en-keyword=T cell exhaustion
kn-keyword=T cell exhaustion
en-keyword=stem-like progenitor exhaustion
kn-keyword=stem-like progenitor exhaustion
en-keyword=terminally differentiated exhaustion
kn-keyword=terminally differentiated exhaustion
en-keyword=PD-1
kn-keyword=PD-1
en-keyword=LAG-3
kn-keyword=LAG-3
en-keyword=TCF1
kn-keyword=TCF1
END

start-ver=1.4
cd-journal=joma
no-vol=4
cd-vols=
no-issue=10
article-no=
start-page=100573
end-page=
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2023
dt-pub=202310
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Immunologic Significance of CD80/CD86 or Major Histocompatibility Complex-II Expression in Thymic Epithelial Tumors
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Introduction: Unresectable or recurrent thymic epithelial tumors (TETs) have a poor prognosis, and treatment options are limited. This study aimed to investigate the immunologic significance of CD80/CD86 or major histocompatibility complex class II (MHC-II) expression in TETs, as potential predictive biomarkers for immune checkpoint inhibitors (ICIs).<br>
Methods: We analyzed CD80, CD86, MHC class I (MHC-I), and MHC-II expression in TETs using immunohistochemistry and investigated their association with T-cell infiltration or ICI efficacy. In addition, we generated CD80- or MHC-II–expressing mouse tumors, evaluated the effects of ICIs, and analyzed tumor-infiltrating lymphocytes. We also performed tumor-rechallenge experiments in vivo.<br>
Results: We found that approximately 50% and 30% of TETs had high expression of CD80/CD86 and MHC-II in tumor cells, respectively, and that this expression was related to T-cell infiltration in clinical samples. In mouse models, both CD80 and MHC-II increase the effects of ICIs. In addition, senescent T cells and long-lived memory precursor effector T cells were significantly decreased and increased, respectively, in tumor-infiltrating lymphocytes from CD80-expressing tumors, and rechallenged tumors were completely rejected after the initial eradication of CD80-expressing tumors by programmed cell death protein 1 blockade. Indeed, patients with CD80-high thymic carcinoma had longer progression-free survival with anti–programmed cell death protein 1 monoclonal antibody.<br>
Conclusions: Half of the TETs had high expression of CD80/CD86 or MHC-II with high T-cell infiltration. These molecules could potentially increase the effects of ICIs, particularly inducing a durable response. CD80/CD86 and MHC-II can be predictive biomarkers of ICIs in TETs, promoting the development of drugs for such TETs.
en-copyright=
kn-copyright=

en-aut-name=IkedaHideki
en-aut-sei=Ikeda
en-aut-mei=Hideki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=NagasakiJoji
en-aut-sei=Nagasaki
en-aut-mei=Joji
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=ShimizuDaiki
en-aut-sei=Shimizu
en-aut-mei=Daiki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=KatsuyaYuki
en-aut-sei=Katsuya
en-aut-mei=Yuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=HorinouchiHidehito
en-aut-sei=Horinouchi
en-aut-mei=Hidehito
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=HosomiYukio
en-aut-sei=Hosomi
en-aut-mei=Yukio
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=TanjiEtsuko
en-aut-sei=Tanji
en-aut-mei=Etsuko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=IwataTakekazu
en-aut-sei=Iwata
en-aut-mei=Takekazu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=ItamiMakiko
en-aut-sei=Itami
en-aut-mei=Makiko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

en-aut-name=KawazuMasahito
en-aut-sei=Kawazu
en-aut-mei=Masahito
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=10
ORCID=

en-aut-name=OheYuichiro
en-aut-sei=Ohe
en-aut-mei=Yuichiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=11
ORCID=

en-aut-name=SuzukiTakuji
en-aut-sei=Suzuki
en-aut-mei=Takuji
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=12
ORCID=

en-aut-name=TogashiYosuke
en-aut-sei=Togashi
en-aut-mei=Yosuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=13
ORCID=

affil-num=1
en-affil=Chiba Cancer Center, Research Institute
kn-affil=

affil-num=2
en-affil=Chiba Cancer Center, Research Institute
kn-affil=

affil-num=3
en-affil=Division of Thoracic Surgery, Chiba Cancer Center
kn-affil=

affil-num=4
en-affil=Department of Experimental Therapeutics, National Cancer Center Hospital
kn-affil=

affil-num=5
en-affil=Department of Thoracic Oncology, National Cancer Center Hospital
kn-affil=

affil-num=6
en-affil=Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital
kn-affil=

affil-num=7
en-affil=Chiba Cancer Center, Research Institute
kn-affil=

affil-num=8
en-affil=Division of Thoracic Surgery, Chiba Cancer Center
kn-affil=

affil-num=9
en-affil=Department of Surgical Pathology, Chiba Cancer Center
kn-affil=

affil-num=10
en-affil=Chiba Cancer Center, Research Institute
kn-affil=

affil-num=11
en-affil=Department of Thoracic Oncology, National Cancer Center Hospital
kn-affil=

affil-num=12
en-affil=Department of Respirology, Graduate School of Medicine, Chiba University
kn-affil=

affil-num=13
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=
en-keyword=Thymic epithelial tumor
kn-keyword=Thymic epithelial tumor
en-keyword=Cancer immunotherapy
kn-keyword=Cancer immunotherapy
en-keyword=CD80/CD86
kn-keyword=CD80/CD86
en-keyword=MHC
kn-keyword=MHC
en-keyword=Memory precursor effector T cell
kn-keyword=Memory precursor effector T cell
END

start-ver=1.4
cd-journal=joma
no-vol=291
cd-vols=
no-issue=6
article-no=
start-page=1119
end-page=1130
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2023
dt-pub=20231020
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Hepatitis C virus NS5B triggers an MDA5-mediated innate immune response by producing dsRNA without the replication of viral genomes
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=During the replication of viral genomes, RNA viruses produce double-stranded RNA (dsRNA), through the activity of their RNA-dependent RNA polymerases (RdRps) as viral replication intermediates. Recognition of viral dsRNA by host pattern recognition receptors – such as retinoic acid-induced gene-I (RIG-I)-like receptors and Toll-like receptor 3 – triggers the production of interferon (IFN)-β via the activation of IFN regulatory factor (IRF)-3. It has been proposed that, during the replication of viral genomes, each of RIG-I and melanoma differentiation-associated gene 5 (MDA5) form homodimers for the efficient activation of a downstream signalling pathway in host cells. We previously reported that, in the non-neoplastic human hepatocyte line PH5CH8, the RdRp NS5B derived from hepatitis C virus (HCV) could induce IFN-β expression by its RdRp activity without the actual replication of viral genomes. However, the exact mechanism by which HCV NS5B produced IFN-β remained unknown. In the present study, we first showed that NS5B derived from another Flaviviridae family member, GB virus B (GBV-B), also possessed the ability to induce IFN-β in PH5CH8 cells. Similarly, HCV NS5B, but not its G317V mutant, which lacks RdRp activity, induced the dimerization of MDA5 and subsequently the activation of IRF-3. Interestingly, immunofluorescence analysis showed that HCV NS5B produced dsRNA. Like HCV NS5B, GBV-B NS5B also triggered the production of dsRNA and subsequently the dimerization of MDA5. Taken together, our results show that HCV NS5B triggers an MDA5-mediated innate immune response by producing dsRNA without the replication of viral genomes in human hepatocytes.
en-copyright=
kn-copyright=

en-aut-name=DansakoHiromichi
en-aut-sei=Dansako
en-aut-mei=Hiromichi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=IkedaMasanori
en-aut-sei=Ikeda
en-aut-mei=Masanori
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=AriumiYasuo
en-aut-sei=Ariumi
en-aut-mei=Yasuo
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=TogashiYosuke
en-aut-sei=Togashi
en-aut-mei=Yosuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=KatoNobuyuki
en-aut-sei=Kato
en-aut-mei=Nobuyuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

affil-num=1
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=2
en-affil=Division of Biological Information Technology, Joint Research Center for Human Retrovirus Infection, Kagoshima University
kn-affil=

affil-num=3
en-affil=Management Department of Biosafety, Laboratory Animal, and Pathogen Bank, National Institute of Infectious Diseases
kn-affil=

affil-num=4
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=5
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=
en-keyword=double-stranded RNA
kn-keyword=double-stranded RNA
en-keyword=hepatitis C virus
kn-keyword=hepatitis C virus
en-keyword=innate immunity
kn-keyword=innate immunity
en-keyword=RIG-I-like receptor
kn-keyword=RIG-I-like receptor
en-keyword=RNA virus
kn-keyword=RNA virus
END

start-ver=1.4
cd-journal=joma
no-vol=154
cd-vols=
no-issue=1
article-no=
start-page=169
end-page=179
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2023
dt-pub=20230823
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Low frequency of intracranial progression in advanced NSCLC patients treated with cancer immunotherapies
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Intracranial metastases are common in nonsmall-cell lung cancer (NSCLC) patients, whose prognosis is very poor. In addition, intracranial progression is common during systemic treatments due to the inability to penetrate central nervous system (CNS) barriers, whereas the intracranial effects of cancer immunotherapies remain unclear. We analyzed clinical data to evaluate the frequency of intracranial progression in advanced NSCLC patients treated with PD-1 blockade therapies compared with those treated without PD-1 blockade therapies, and found that the frequency of intracranial progression in advanced NSCLC patients treated with PD-1 blockade therapies was significantly lower than that in patients treated with cytotoxic chemotherapies. In murine models, intracranial rechallenged tumors after initial rejection by PD-1 blockade were suppressed. Accordingly, long-lived memory precursor effector T cells and antigen-specific T cells were increased by PD-1 blockade in intracranial lesions. However, intracranial rechallenged different tumors are not suppressed. Our results indicate that cancer immunotherapies can prevent intracranial progression, maintaining long-term effects intracranially as well as systemically. If intracranial recurrence occurs during the treatment with PD-1 blockade therapies, aggressive local therapies could be worthwhile.
en-copyright=
kn-copyright=

en-aut-name=KemmotsuNaoya
en-aut-sei=Kemmotsu
en-aut-mei=Naoya
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=NinomiyaKiichiro
en-aut-sei=Ninomiya
en-aut-mei=Kiichiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=KunimasaKei
en-aut-sei=Kunimasa
en-aut-mei=Kei
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=IshinoTakamasa
en-aut-sei=Ishino
en-aut-mei=Takamasa
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=NagasakiJoji
en-aut-sei=Nagasaki
en-aut-mei=Joji
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=OtaniYoshihiro
en-aut-sei=Otani
en-aut-mei=Yoshihiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=MichiueHiroyuki
en-aut-sei=Michiue
en-aut-mei=Hiroyuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=IchiharaEiki
en-aut-sei=Ichihara
en-aut-mei=Eiki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=OhashiKadoaki
en-aut-sei=Ohashi
en-aut-mei=Kadoaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

en-aut-name=InoueTakako
en-aut-sei=Inoue
en-aut-mei=Takako
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=10
ORCID=

en-aut-name=TamiyaMotohiro
en-aut-sei=Tamiya
en-aut-mei=Motohiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=11
ORCID=

en-aut-name=SakaiKazuko
en-aut-sei=Sakai
en-aut-mei=Kazuko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=12
ORCID=

en-aut-name=UedaYouki
en-aut-sei=Ueda
en-aut-mei=Youki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=13
ORCID=

en-aut-name=DansakoHiromichi
en-aut-sei=Dansako
en-aut-mei=Hiromichi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=14
ORCID=

en-aut-name=NishioKazuto
en-aut-sei=Nishio
en-aut-mei=Kazuto
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=15
ORCID=

en-aut-name=KiuraKatsuyuki
en-aut-sei=Kiura
en-aut-mei=Katsuyuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=16
ORCID=

en-aut-name=DateIsao
en-aut-sei=Date
en-aut-mei=Isao
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=17
ORCID=

en-aut-name=TogashiYosuke
en-aut-sei=Togashi
en-aut-mei=Yosuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=18
ORCID=

affil-num=1
en-affil=Department of Tumor Microenvironment, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=2
en-affil=Department of Respiratory Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=3
en-affil=Department of Thoracic Oncology, Osaka International Cancer Institute
kn-affil=

affil-num=4
en-affil=Department of Tumor Microenvironment, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=5
en-affil=Department of Tumor Microenvironment, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=6
en-affil=Department of Neurological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=7
en-affil=Department of Neurological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=8
en-affil=Department of Respiratory Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=9
en-affil=Department of Respiratory Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=10
en-affil=Department of Thoracic Oncology, Osaka International Cancer Institute
kn-affil=

affil-num=11
en-affil=Department of Thoracic Oncology, Osaka International Cancer Institute
kn-affil=

affil-num=12
en-affil=Department of Genome Biology, Kindai University Faculty of Medicine
kn-affil=

affil-num=13
en-affil=Department of Tumor Microenvironment, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=14
en-affil=Department of Tumor Microenvironment, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=15
en-affil=Department of Genome Biology, Kindai University Faculty of Medicine
kn-affil=

affil-num=16
en-affil=Department of Respiratory Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=17
en-affil=Department of Neurological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=18
en-affil=Department of Tumor Microenvironment, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=
en-keyword=cancer immunotherapy
kn-keyword=cancer immunotherapy
en-keyword=intracranial metastasis
kn-keyword=intracranial metastasis
en-keyword=intracranial progression
kn-keyword=intracranial progression
en-keyword=memory precursor effector T cell
kn-keyword=memory precursor effector T cell
en-keyword=nonsmall-cell lung cancer
kn-keyword=nonsmall-cell lung cancer
END

start-ver=1.4
cd-journal=joma
no-vol=2
cd-vols=
no-issue=7
article-no=
start-page=739
end-page=753
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2022
dt-pub=20220728
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Mixed Response to Cancer Immunotherapy is Driven by Intratumor Heterogeneity and Differential Interlesion Immune Infiltration
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Some patients experience mixed response to immunotherapy, whose biological mechanisms and clinical impact have been obscure. We obtained two tumor samples from lymph node (LN) metastatic lesions in a same patient. Whole exome sequencing for the both tumors and single-cell sequencing for the both tumor-infiltrating lymphocytes (TIL) demonstrated a significant difference in tumor clonality and TILs' characteristics, especially exhausted T-cell clonotypes, although a close relationship between the tumor cell and T-cell clones were observed as a response of an overlapped exhausted T-cell clone to an overlapped neoantigen. To mimic the clinical setting, we generated a mouse model of several clones from a same tumor cell line. Similarly, differential tumor clones harbored distinct TILs, and one responded to programmed cell death protein 1 (PD-1) blockade but the other did not in this model. We further conducted cohort study (n = 503) treated with PD-1 blockade monotherapies to investigate the outcome of mixed response. Patients with mixed responses to PD-1 blockade had a poor prognosis in our cohort. Particularly, there were significant differences in both tumor and T-cell clones between the primary and LN lesions in a patient who experienced tumor response to anti-PD-1 mAb followed by disease progression in only LN metastasis. Our results underscore that intertumoral heterogeneity alters characteristics of TILs even in the same patient, leading to mixed response to immunotherapy and significant difference in the outcome.<br>
Significance: Several patients experience mixed responses to immunotherapies, but the biological mechanisms and clinical significance remain unclear. Our results from clinical and mouse studies underscore that intertumoral heterogeneity alters characteristics of TILs even in the same patient, leading to mixed response to immunotherapy and significant difference in the outcome.
en-copyright=
kn-copyright=

en-aut-name=MorinagaTakao
en-aut-sei=Morinaga
en-aut-mei=Takao
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=InozumeTakashi
en-aut-sei=Inozume
en-aut-mei=Takashi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=KawazuMasahito
en-aut-sei=Kawazu
en-aut-mei=Masahito
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=UedaYouki
en-aut-sei=Ueda
en-aut-mei=Youki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=SaxNicolas
en-aut-sei=Sax
en-aut-mei=Nicolas
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=YamashitaKazuo
en-aut-sei=Yamashita
en-aut-mei=Kazuo
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=KawashimaShusuke
en-aut-sei=Kawashima
en-aut-mei=Shusuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=NagasakiJoji
en-aut-sei=Nagasaki
en-aut-mei=Joji
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=UenoToshihide
en-aut-sei=Ueno
en-aut-mei=Toshihide
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

en-aut-name=LinJason
en-aut-sei=Lin
en-aut-mei=Jason
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=10
ORCID=

en-aut-name=OharaYuuki
en-aut-sei=Ohara
en-aut-mei=Yuuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=11
ORCID=

en-aut-name=KuwataTakeshi
en-aut-sei=Kuwata
en-aut-mei=Takeshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=12
ORCID=

en-aut-name=YukamiHiroki
en-aut-sei=Yukami
en-aut-mei=Hiroki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=13
ORCID=

en-aut-name=KawazoeAkihito
en-aut-sei=Kawazoe
en-aut-mei=Akihito
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=14
ORCID=

en-aut-name=ShitaraKohei
en-aut-sei=Shitara
en-aut-mei=Kohei
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=15
ORCID=

en-aut-name=Honobe-TabuchiAkiko
en-aut-sei=Honobe-Tabuchi
en-aut-mei=Akiko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=16
ORCID=

en-aut-name=OhnumaTakehiro
en-aut-sei=Ohnuma
en-aut-mei=Takehiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=17
ORCID=

en-aut-name=KawamuraTatsuyoshi
en-aut-sei=Kawamura
en-aut-mei=Tatsuyoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=18
ORCID=

en-aut-name=UmedaYoshiyasu
en-aut-sei=Umeda
en-aut-mei=Yoshiyasu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=19
ORCID=

en-aut-name=KawaharaYu
en-aut-sei=Kawahara
en-aut-mei=Yu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=20
ORCID=

en-aut-name=NakamuraYasuhiro
en-aut-sei=Nakamura
en-aut-mei=Yasuhiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=21
ORCID=

en-aut-name=KiniwaYukiko
en-aut-sei=Kiniwa
en-aut-mei=Yukiko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=22
ORCID=

en-aut-name=MoritaAyako
en-aut-sei=Morita
en-aut-mei=Ayako
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=23
ORCID=

en-aut-name=IchiharaEiki
en-aut-sei=Ichihara
en-aut-mei=Eiki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=24
ORCID=

en-aut-name=KiuraKatsuyuki
en-aut-sei=Kiura
en-aut-mei=Katsuyuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=25
ORCID=

en-aut-name=EnokidaTomohiro
en-aut-sei=Enokida
en-aut-mei=Tomohiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=26
ORCID=

en-aut-name=TaharaMakoto
en-aut-sei=Tahara
en-aut-mei=Makoto
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=27
ORCID=

en-aut-name=HasegawaYoshinori
en-aut-sei=Hasegawa
en-aut-mei=Yoshinori
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=28
ORCID=

en-aut-name=ManoHiroyuki
en-aut-sei=Mano
en-aut-mei=Hiroyuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=29
ORCID=

en-aut-name=SuzukiYutaka
en-aut-sei=Suzuki
en-aut-mei=Yutaka
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=30
ORCID=

en-aut-name=NishikawaHiroyoshi
en-aut-sei=Nishikawa
en-aut-mei=Hiroyoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=31
ORCID=

en-aut-name=TogashiYosuke
en-aut-sei=Togashi
en-aut-mei=Yosuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=32
ORCID=

affil-num=1
en-affil=Chiba Cancer Center, Research Institute
kn-affil=

affil-num=2
en-affil=Chiba Cancer Center, Research Institute
kn-affil=

affil-num=3
en-affil=Chiba Cancer Center, Research Institute
kn-affil=

affil-num=4
en-affil=Department of Tumor Microenvironment, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=5
en-affil=KOTAI Biotechnologies Inc
kn-affil=

affil-num=6
en-affil=KOTAI Biotechnologies Inc
kn-affil=

affil-num=7
en-affil=Chiba Cancer Center, Research Institute
kn-affil=

affil-num=8
en-affil=Department of Tumor Microenvironment, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=9
en-affil=Division of Cellular Signaling, National Cancer Center Research Institute
kn-affil=

affil-num=10
en-affil=Chiba Cancer Center, Research Institute
kn-affil=

affil-num=11
en-affil=Department of Pathology, National Cancer Center Hospital East
kn-affil=

affil-num=12
en-affil=Department of Genetic Medicineand Services, National Cancer Center Hospital East
kn-affil=

affil-num=13
en-affil=Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East
kn-affil=

affil-num=14
en-affil=Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East
kn-affil=

affil-num=15
en-affil=Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East
kn-affil=

affil-num=16
en-affil=Department of Dermatology, University of Yamanashi
kn-affil=

affil-num=17
en-affil=Department of Dermatology, University of Yamanashi
kn-affil=

affil-num=18
en-affil=Department of Dermatology, University of Yamanashi
kn-affil=

affil-num=19
en-affil=Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center
kn-affil=

affil-num=20
en-affil=Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center
kn-affil=

affil-num=21
en-affil=Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center
kn-affil=

affil-num=22
en-affil=Department of Dermatology, Shinshu University School of Medicine 
kn-affil=

affil-num=23
en-affil=Department of Allergy and Respiratory Medicine, Okayama University Hospital
kn-affil=

affil-num=24
en-affil=Department of Allergy and Respiratory Medicine, Okayama University Hospital
kn-affil=

affil-num=25
en-affil=Department of Allergy and Respiratory Medicine, Okayama University Hospital
kn-affil=

affil-num=26
en-affil=Department of Head and Neck Medical Oncology, National Cancer Center Hospital East
kn-affil=

affil-num=27
en-affil=Department of Head and Neck Medical Oncology, National Cancer Center Hospital East
kn-affil=

affil-num=28
en-affil=Department of Applied Genomics, Kazusa DNA Research Institute
kn-affil=

affil-num=29
en-affil=Division of Cellular Signaling, National Cancer Center Research Institute
kn-affil=

affil-num=30
en-affil=Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo
kn-affil=

affil-num=31
en-affil=Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center
kn-affil=

affil-num=32
en-affil=Department of Tumor Microenvironment, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences
kn-affil=
END

start-ver=1.4
cd-journal=joma
no-vol=11
cd-vols=
no-issue=7
article-no=
start-page=895
end-page=908
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2023
dt-pub=20230705
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=High Expression of MHC Class I Overcomes Cancer Immunotherapy Resistance Due to IFNγ Signaling Pathway Defects
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=IFNγ signaling pathway defects are well-known mechanisms of resistance to immune checkpoint inhibitors. However, conflicting data have been reported, and the detailed mechanisms remain unclear. In this study, we have demonstrated that resistance to immune checkpoint inhibitors owing to IFNγ signaling pathway defects may be primarily caused by reduced MHC-I expression rather than by the loss of inhibitory effects on cellular proliferation or decreased chemokine production. In particular, we found that chemokines that recruit effector T cells were mainly produced by immune cells rather than cancer cells in the tumor microenvironment of a mouse model, with defects in IFNγ signaling pathways. Furthermore, we found a response to immune checkpoint inhibitors in a patient with JAK-negative head and neck squamous cell carcinoma whose HLA-I expression level was maintained. In addition, CRISPR screening to identify molecules associated with elevated MHC-I expression independent of IFNγ signaling pathways demonstrated that guanine nucleotide-binding protein subunit gamma 4 (GNG4) maintained MHC-I expression via the NF-κB signaling pathway. Our results indicate that patients with IFNγ signaling pathway defects are not always resistant to immune checkpoint inhibitors and highlight the importance of MHC-I expression among the pathways and the possibility of NF-κB–targeted therapies to overcome such resistance.
en-copyright=
kn-copyright=

en-aut-name=KawaseKatsushige
en-aut-sei=Kawase
en-aut-mei=Katsushige
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=KawashimaShusuke
en-aut-sei=Kawashima
en-aut-mei=Shusuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=NagasakiJoji
en-aut-sei=Nagasaki
en-aut-mei=Joji
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=InozumeTakashi
en-aut-sei=Inozume
en-aut-mei=Takashi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=TanjiEtsuko
en-aut-sei=Tanji
en-aut-mei=Etsuko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=KawazuMasahito
en-aut-sei=Kawazu
en-aut-mei=Masahito
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=HanazawaToyoyuki
en-aut-sei=Hanazawa
en-aut-mei=Toyoyuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=TogashiYosuke
en-aut-sei=Togashi
en-aut-mei=Yosuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

affil-num=1
en-affil=Division of Cell Therapy, Chiba Cancer Center Research Institute
kn-affil=

affil-num=2
en-affil=Division of Cell Therapy, Chiba Cancer Center Research Institute
kn-affil=

affil-num=3
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=4
en-affil=Division of Cell Therapy, Chiba Cancer Center Research Institute
kn-affil=

affil-num=5
en-affil=Division of Cell Therapy, Chiba Cancer Center Research Institute
kn-affil=

affil-num=6
en-affil=Division of Cell Therapy, Chiba Cancer Center Research Institute
kn-affil=

affil-num=7
en-affil=Department of Otorhinolaryngology/Head & Neck Surgery, Graduate School of Medicine, Chiba University
kn-affil=

affil-num=8
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=
END

start-ver=1.4
cd-journal=joma
no-vol=114
cd-vols=
no-issue=10
article-no=
start-page=3848
end-page=3856
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2023
dt-pub=20230723
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Combination therapy with hydrogen peroxide and irradiation promotes an abscopal effect in mouse models
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Hydrogen peroxide (H2O2) induces oxidative stress and cytotoxicity, and can be used for treating cancers in combination with radiotherapy. A product comprising H2O2 and sodium hyaluronate has been developed as a radiosensitizer. However, the effects of H2O2 on antitumor immunity remain unclear. To investigate the effects of H2O2, especially the abscopal effect when combined with radiotherapy (RT), we implanted murine tumor cells simultaneously in two locations in mouse models: the hind limb and back. H2O2 mixed with sodium hyaluronate was injected intratumorally, followed by irradiation only at the hind limb lesion. No treatment was administered to the back lesion. The H2O2/RT combination significantly reduced tumor growth at the noninjected/nonirradiated site in the back lesion, whereas H2O2 or RT individually did not reduce tumor growth. Flow cytometric analyses of the tumor-draining lymph nodes in the injected/irradiated areas showed that the number of dendritic cells increased significantly with maturation in the H2O2/RT combination group. In addition, analyses of tumor-infiltrating lymphocytes showed that the number of CD8+ (cluster of differentiation 8) T cells and the frequency of IFN-γ+ (interferon gamma) CD8+ T cells were higher in the noninjected/nonirradiated tumors in the H2O2/RT group compared to those in the other groups. PD-1 (programmed death receptor 1) blockade further increased the antitumor effect against noninjected/nonirradiated tumors in the H2O2/RT group. Intratumoral injection of H2O2 combined with RT therefore induces an abscopal effect by activating antitumor immunity, which can be further enhanced by PD-1 blockade. These findings promote the development of H2O2/RT therapy combined with cancer immunotherapies, even for advanced cancers.
en-copyright=
kn-copyright=

en-aut-name=KemmotsuNaoya
en-aut-sei=Kemmotsu
en-aut-mei=Naoya
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=ZhuLi
en-aut-sei=Zhu
en-aut-mei=Li
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=NagasakiJoji
en-aut-sei=Nagasaki
en-aut-mei=Joji
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=OtaniYoshihiro
en-aut-sei=Otani
en-aut-mei=Yoshihiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=UedaYouki
en-aut-sei=Ueda
en-aut-mei=Youki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=DansakoHiromichi
en-aut-sei=Dansako
en-aut-mei=Hiromichi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=FangYue
en-aut-sei=Fang
en-aut-mei=Yue
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=DateIsao
en-aut-sei=Date
en-aut-mei=Isao
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=TogashiYosuke
en-aut-sei=Togashi
en-aut-mei=Yosuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

affil-num=1
en-affil=Department of Tumor Microenvironment, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=2
en-affil=Department of Tumor Microenvironment, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=3
en-affil=Department of Tumor Microenvironment, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=4
en-affil=Department of Neurological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=5
en-affil=Department of Tumor Microenvironment, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=6
en-affil=Department of Tumor Microenvironment, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=7
en-affil=Department of Microbial and Biochemical Pharmacy, School of Pharmacy, China Medical University
kn-affil=

affil-num=8
en-affil=Department of Neurological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=9
en-affil=Department of Tumor Microenvironment, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=
en-keyword=abscopal effect
kn-keyword=abscopal effect
en-keyword=dendritic cell
kn-keyword=dendritic cell
en-keyword=hydrogen peroxide
kn-keyword=hydrogen peroxide
en-keyword=radiosensitizer
kn-keyword=radiosensitizer
en-keyword=radiotherapy
kn-keyword=radiotherapy
en-keyword=tumor-draining lymph node
kn-keyword=tumor-draining lymph node
END

start-ver=1.4
cd-journal=joma
no-vol=
cd-vols=
no-issue=
article-no=
start-page=
end-page=
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2023
dt-pub=20230210
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Activated CTLA-4-independent immunosuppression of Treg cells disturbs CTLA-4 blockade-mediated antitumor immunity
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Combination therapy with anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death-1 (PD-1) monoclonal antibodies (mAbs) has dramatically improved the prognosis of patients with multiple types of cancer, including renal cell carcinoma (RCC). However, more than half of RCC patients fail to respond to this therapy. Regulatory T cells (Treg cells) are a subset of highly immunosuppressive CD4(+) T cells that promote the immune escape of tumors by suppressing effector T cells in the tumor microenvironment (TME) through various mechanisms. CTLA-4 is constitutively expressed in Treg cells and is regarded as a key molecule for Treg-cell-mediated immunosuppressive functions, suppressing antigen-presenting cells by binding to CD80/CD86. Reducing Treg cells in the TME with an anti-CTLA-4 mAb with antibody-dependent cellular cytotoxicity (ADCC) activity is considered an essential mechanism to achieve tumor regression. In contrast, we demonstrated that CTLA-4 blockade without ADCC activity enhanced CD28 costimulatory signaling pathways in Treg cells and promoted Treg-cell proliferation in mouse models. CTLA-4 blockade also augmented CTLA-4-independent immunosuppressive functions, including cytokine production, leading to insufficient antitumor effects. Similar results were also observed in human peripheral blood lymphocytes and tumor-infiltrating lymphocytes from patients with RCC. Our findings highlight the importance of Treg-cell depletion to achieve tumor regression in response to CTLA-4 blockade therapies.
en-copyright=
kn-copyright=

en-aut-name=WatanabeTomofumi
en-aut-sei=Watanabe
en-aut-mei=Tomofumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=IshinoTakamasa
en-aut-sei=Ishino
en-aut-mei=Takamasa
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=UedaYouki
en-aut-sei=Ueda
en-aut-mei=Youki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=NagasakiJoji
en-aut-sei=Nagasaki
en-aut-mei=Joji
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=SadahiraTakuya
en-aut-sei=Sadahira
en-aut-mei=Takuya
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=DansakoHiromichi
en-aut-sei=Dansako
en-aut-mei=Hiromichi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=ArakiMotoo
en-aut-sei=Araki
en-aut-mei=Motoo
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=TogashiYosuke
en-aut-sei=Togashi
en-aut-mei=Yosuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

affil-num=1
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=2
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=3
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=4
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=5
en-affil=Department of Urology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=6
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=7
en-affil=Department of Urology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=8
en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=
en-keyword=antibody-dependent cell cytotoxicity
kn-keyword=antibody-dependent cell cytotoxicity
en-keyword=cytotoxic T-lymphocyte-associated antigen 4
kn-keyword=cytotoxic T-lymphocyte-associated antigen 4
en-keyword=immune checkpoint inhibitors
kn-keyword=immune checkpoint inhibitors
en-keyword=regulatory T cell
kn-keyword=regulatory T cell
en-keyword=renal cell carcinoma
kn-keyword=renal cell carcinoma
END

start-ver=1.4
cd-journal=joma
no-vol=
cd-vols=
no-issue=
article-no=
start-page=
end-page=
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2023
dt-pub=20230202
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Somatic mutations can induce a noninflamed tumour microenvironment via their original gene functions, despite deriving neoantigens
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Background<br>
Identifying biomarkers to predict immune checkpoint inhibitor (ICI) efficacy is warranted. Considering that somatic mutation-derived neoantigens induce strong immune responses, patients with a high tumour mutational burden reportedly tend to respond to ICIs. However, there are several conflicting data. Therefore, we focused on the original function of neoantigenic mutations and their impact on the tumour microenvironment (TME).<br>
<br>
Methods<br>
We evaluated 88 high-frequency microsatellite instability (MSI-H) colorectal cancers and analysed the function of the identified neoantigenic mutations and their influence on programmed cell death 1 (PD-1) blockade efficacy. The results were validated using The Cancer Genome Atlas (TCGA) datasets.<br>
<br>
Results<br>
We identified frameshift mutations in RNF43 as a common neoantigenic gene mutation in MSI-H tumours. However, loss-of-function RNF43 mutations induced noninflamed TME by activating the WNT/β-catenin signalling pathway. In addition, loss of RNF43 function induced resistance to PD-1 blockade even in neoantigen-rich tumours. TCGA dataset analyses demonstrated that passenger rather than driver gene mutations were related to the inflamed TME in diverse cancer types.<br>
<br>
Conclusions<br>
We propose a novel concept of “paradoxical neoantigenic mutations” that can induce noninflamed TME through their original gene functions, despite deriving neoantigens, suggesting the significance of qualities as well as quantities in neoantigenic mutations.
en-copyright=
kn-copyright=

en-aut-name=IshinoTakamasa
en-aut-sei=Ishino
en-aut-mei=Takamasa
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=KawashimaShusuke
en-aut-sei=Kawashima
en-aut-mei=Shusuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=TanjiEtsuko
en-aut-sei=Tanji
en-aut-mei=Etsuko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=UenoToshihide
en-aut-sei=Ueno
en-aut-mei=Toshihide
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=UedaYouki
en-aut-sei=Ueda
en-aut-mei=Youki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=OgasawaraSadahisa
en-aut-sei=Ogasawara
en-aut-mei=Sadahisa
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=SatoKazuhito
en-aut-sei=Sato
en-aut-mei=Kazuhito
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=ManoHiroyuki
en-aut-sei=Mano
en-aut-mei=Hiroyuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=IshiharaSoichiro
en-aut-sei=Ishihara
en-aut-mei=Soichiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

en-aut-name=KatoNaoya
en-aut-sei=Kato
en-aut-mei=Naoya
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=10
ORCID=

en-aut-name=KawazuMasahito
en-aut-sei=Kawazu
en-aut-mei=Masahito
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=11
ORCID=

en-aut-name=TogashiYosuke
en-aut-sei=Togashi
en-aut-mei=Yosuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=12
ORCID=

affil-num=1
en-affil=Department of Tumor Microenvironment, Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=2
en-affil=Division of Cell Therapy, Chiba Cancer Center Research Institute
kn-affil=

affil-num=3
en-affil=Division of Cell Therapy, Chiba Cancer Center Research Institute
kn-affil=

affil-num=4
en-affil=Division of Cellular Signaling, National Cancer Center Research Institute
kn-affil=

affil-num=5
en-affil=Department of Tumor Microenvironment, Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=6
en-affil=Department of Gastroenterology, Graduate School of Medicine, Chiba University
kn-affil=

affil-num=7
en-affil=Department of Surgical Oncology, Graduate School of Medicine, The University of Tokyo
kn-affil=

affil-num=8
en-affil=Division of Cellular Signaling, National Cancer Center Research Institute
kn-affil=

affil-num=9
en-affil=Department of Surgical Oncology, Graduate School of Medicine, The University of Tokyo
kn-affil=

affil-num=10
en-affil=Department of Gastroenterology, Graduate School of Medicine, Chiba University
kn-affil=

affil-num=11
en-affil=Division of Cell Therapy, Chiba Cancer Center Research Institute
kn-affil=

affil-num=12
en-affil=Department of Tumor Microenvironment, Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences
kn-affil=
END

start-ver=1.4
cd-journal=joma
no-vol=133
cd-vols=
no-issue=3
article-no=
start-page=151
end-page=157
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2021
dt-pub=20211201
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=Cancer-immunotherapy biomarkers in the tumor microenvironment
kn-title=腫瘍微小環境とがん免疫療法のバイオマーカー
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=
en-copyright=
kn-copyright=

en-aut-name=TogashiYosuke
en-aut-sei=Togashi
en-aut-mei=Yosuke
kn-aut-name=冨樫庸介
kn-aut-sei=冨樫
kn-aut-mei=庸介
aut-affil-num=1
ORCID=

affil-num=1
en-affil=Department of Tumor Microenvironment, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=岡山大学学術研究院医歯薬学域　腫瘍微小環境学
en-keyword=tumor microenvironment
kn-keyword=tumor microenvironment
en-keyword=cancer immunology
kn-keyword=cancer immunology
en-keyword=tumor-infiltrating T cell
kn-keyword=tumor-infiltrating T cell
en-keyword=PD-1/PD-L1
kn-keyword=PD-1/PD-L1
END