{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T19:40:58Z","timestamp":1793734858921,"version":"4.6.1"},"reference-count":68,"publisher":"Springer Science and Business Media LLC","issue":"7854","license":[{"start":{"date-parts":[[2021,3,24]],"date-time":"2021-03-24T00:00:00Z","timestamp":1616544000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,3,24]],"date-time":"2021-03-24T00:00:00Z","timestamp":1616544000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nature"],"published-print":{"date-parts":[[2021,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Hepatocellular carcinoma (HCC) can have viral or non-viral causes\n                    <jats:sup>1\u20135<\/jats:sup>\n                    . Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need\n                    <jats:sup>6,7<\/jats:sup>\n                    . Here we report the progressive accumulation of exhausted, unconventionally activated CD8\n                    <jats:sup>+<\/jats:sup>\n                    PD1\n                    <jats:sup>+<\/jats:sup>\n                    T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8\n                    <jats:sup>+<\/jats:sup>\n                    PD1\n                    <jats:sup>+<\/jats:sup>\n                    T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH\u2013HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8\n                    <jats:sup>+<\/jats:sup>\n                    PD1\n                    <jats:sup>+<\/jats:sup>\n                    CXCR6\n                    <jats:sup>+<\/jats:sup>\n                    , TOX\n                    <jats:sup>+<\/jats:sup>\n                    , and TNF\n                    <jats:sup>+<\/jats:sup>\n                    T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells or TNF neutralization, suggesting that CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells help to induce NASH\u2013HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8\n                    <jats:sup>+<\/jats:sup>\n                    PD1\n                    <jats:sup>+<\/jats:sup>\n                    T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH\u2013HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.\n                  <\/jats:p>","DOI":"10.1038\/s41586-021-03362-0","type":"journal-article","created":{"date-parts":[[2021,3,24]],"date-time":"2021-03-24T13:06:44Z","timestamp":1616591204000},"page":"450-456","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1223,"title":["NASH limits anti-tumour surveillance in immunotherapy-treated HCC"],"prefix":"10.1038","volume":"592","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0542-2638","authenticated-orcid":false,"given":"Dominik","family":"Pfister","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3837-270X","authenticated-orcid":false,"given":"Nicol\u00e1s 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D.P. works currently for Novo Nordisk. M. Szydlowksa works currently for Astra Zeneca. M.K. received honoraria from BMS as consultant and is an investigator for AstraZeneca and BMS. A.V. has served as consultant for Roche, Bayer, Lilly, BMS, Eisai, and Ipsen; has received speaking fees form Roche, Bayer, Lilly, BMS, Eisai, and Ipsen; and is an investigator for Roche, Bayer, Lilly, BMS, Eisai, and Ipsen. F.H. has received travel support from Bayer, Abbvie, and Gilead. M.P.-R. is an advisor\/consultant for Astra Zeneca, Bayer, BMS, Eisai, Ipsen, Lilly, and MSD; has served as a speaker for Bayer, Eisai, and Lilly; and is an investigator for Bayer, BMS, Exelixis, and Lilly. F.F. has received travel support from Abbvie and Novartis. O.W. has served as consultant for Amgen, Bayer, BMS, Celgene, Eisai, Merck, Novartis, Roche, Servier, and Shire; has served as a speaker for Abbvie, Bayer, BMS, Celgene, Falk, Ipsen, Novartis, Roche, and Shire; and has received travel support from Abbvie, BMS, Ipsen, Novartis, and Servier. J.T. has served as consultant for Amgen, Bayer, BMS, Eisai, Lilly, Merck Serono, MSD, Ipsen, and Roche; has received travel support from BMS and Ipsen; has received speaking fees from Amgen, Bayer, BMS, Eisai, Lilly, Merck Serono, MSD, Ipsen, and Roche; and is an investigator for Amgen, Bayer, BMS, Eisai, Lilly, Merck Serono, MSD, Ipsen, and Roche. K.S. has served as consultant for Ipsen and Bayer; and conducts studies for Bayer, Roche, Lilly, MSD, and BMS. H.W. has served as speaker for Bayer, Eisai, and Ipsen; has served as a consultant for Bayer, Eisai, Lilly, BMS, Roche, and Ipsen; and conducts studies for Bayer, Roche, Lilly, MSD, and BMS. A. Weberis an advisor for BMS, Wako, Eisai, Roche, and Amgen. J.C.M. has received consulting honoraria from Abbvie, Bayer, BMS, Eisai, Gilead, Incyte, Intercept and MSD for work performed outside the current study. J.M.L. is receiving research support from Bayer HealthCare Pharmaceuticals, Eisai Inc, Bristol-Myers Squibb, Boehringer-Ingelheim and Ipsen, and consulting fees from Eli Lilly, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb, Eisai Inc, Celsion Corporation, Exelixis, Merck, Ipsen, Genentech, Roche, Glycotest, Leerink Swann LLC, Fortress Biotech, Nucleix, Can-Fite Biopharma, Sirtex, Mina Alpha Ltd and AstraZeneca. J.M.S. serves as a consultant for Intercept Pharmaceuticals, Genfit, Gilead Sciences, BMS, Madrigal, Novartis, Pfizer, Roche, and Siemens-Healthineers; and has received research funding from Gilead Sciences. D.J.P. has received lecture fees from ViiV Healthcare and Bayer Healthcare; travel expenses from BMS and Bayer Healthcare; consulting fees from Mina Therapeutics, EISAI, Roche and Astra Zeneca; and research funding (to institution) from MSD and BMS. J.-F.D. has served on advisory committees for Abbvie, Bayer, Bristol-Myers Squibb, Falk, Genfit, Genkyotex, Gilead Sciences, HepaRegenix, Intercept, Lilly, Merck, and Novartis; and has spoken or taught at Bayer, Bristol-Myers Squibb, Intercept, Genfit, Gilead Sciences, Novartis, and Roche. L.R. has received consulting fees from Amgen, ArQule, Astra Zeneca, Basilea, Bayer, Celgene, Eisai, Exelixis, Hengrui, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, and Sanofi; lectures fees from AbbVie, Amgen, Eisai, Gilead, Incyte, Ipsen, Lilly, Roche, Sanofi; travel expenses from Ipsen; and institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, and Roche. N.P. has received consulting fees from Amgen, Merck Serono, and Servier; lectures fees from AbbVie, Gilead and Lilly; travel expenses from Amgen and ArQule; and institutional research funding from Basilea, Merck Serono and Servier. T.P. has received institutional research funding from Lilly. D.G.D. has received consultant fees from Bayer, Simcere, Surface Oncology and BMS; and research grants from Bayer, Exelixis and BMS. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}