Hepatocellular carcinoma (HCC) can have viral or non-viral causes1-5. 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 need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ 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-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ 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-HCC, 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.
Förderungen'Deutsche Forschungsgemeinschaft' (DFG) Rio Hortega grant from the ISCIII HEPCAR Generalitat de Catalunya/AGAUR Spanish National Health Institute Samuel Waxman Cancer Research Foundation Tisch Cancer Institute NCI Cancer Center Support Grant European Social Fund AECC Swiss National Science Foundation (SNF) German Research Foundation Helmholtz-Gemeinschaft, Zukunftsthema 'Immunology and Inflammation' German-Israeli Cooperation in Cancer Research (DKFZ-MOST) Deutsche Krebshilfe projects Research Foundation Flanders (FWO) Wilhelm Sander-Stiftung ERC Consolidator grant (HepatoMetaboPath) US Department of Defense European Commission (EC)/Horizon 2020 Program (HEPCAR) Thompson Family Foundation European Research Council consolidator grant (ERC-COG) HHMI international scholar award Chan Zuckerberg Initiative (CZI) Newcastle NIHR Biomedical Research Centre LITMUS (Liver Investigation: Testing Marker Utility in Steatohepatitis) consortium - Innovative Medicines Initiative (IMI2) Program of the European Union EPoS (Elucidating Pathways of Steatohepatitis) consortium - Horizon 2020 Framework Program of the European Union EMBO LT fellowship MRA established investigator award Israel Science Foundation Ernest and Bonnie Beutler Research Program for Excellence in Genomic Medicine Fundacion Cientifica de la Asociacion Espanola Contra el Cancer (HUNTER) Fondazione AIRC Cancer Research UK SCA award of the Wolfson Foundation Adelis Foundation NeuroMac DFG/Transregional Collaborative Research Center grant Helen and Martin Kimmel award for innovative investigation 'Deutsche Forschungsgemeinschaft' (DFG, Bonn Germany) through Emmy Noether program Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ) 360372040 BMBF Helmholtz Future topic Inflammation and Immunology Dangel Stiftung Bangerter-Rhyner Stiftung Stiftung zur Krebsbekampfung Norwegian PSC Research Center Canica Holding Research Grant SNF Project Grant International Progressive MS Alliance/NMSS National Cancer Institute Rainer Hoenig Stiftung SFBTR1335 314905040 SFB/TR 209 272983813 SFBTR179 SFB 1335 CW+ Horizon 2020 grant (Hepcar) University Research Priority Program (URPP) postdoctoral fellowship Swiss Cancer League DFG Swiss Foundation against Liver Cancer Swiss National Foundation German Cancer Aid Westminster Medical School Research Trust ASCO/Conquer Cancer Foundation Global Oncology Young Investigator Award 2019 Wellcome Trust Strategic Fund Elke-Kroner-Fresenius foundation Deutsche Forschungsgemeinschaft Swiss National Science Foundation German Cancer Research Center (DKTK) European Research Council (CholangioConcept) Landesstiftung Baden-Wuerttemberg DFG under Germany's excellence strategy German Ministry for Education and Research (BMBF) Israel's Ministry of Science, Technology and Space (MOST)