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00925njm 22002777a 4500 dc Pfister, Dominik author Núñez, Nicolás Gonzalo author Pinyol, Roser author Govaere, Olivier author Pinter, Matthias author Szydlowska, Marta author Gupta, Revant author Qiu, Mengjie author Deczkowska, Aleksandra author Weiner, Assaf author Müller, Florian author Sinha, Ankit author Friebel, Ekaterina author Engleitner, Thomas author Lenggenhager, Daniela author Moncsek, Anja author Heide, Danijela author Stirm, Kristin author Kosla, Jan author Kotsiliti, Eleni author Leone, Valentina author Dudek, Michael author Yousuf, Suhail author Inverso, Donato author Singh, Indrabahadur author Teijeiro, Ana author Castet, Florian author Montironi, Carla author Haber, Philipp K author Tiniakos, Dina author Bedossa, Pierre author Cockell, Simon author Younes, Ramy author Vacca, Michele author Marra, Fabio author Schattenberg, Jörn M author Allison, Michael author Bugianesi, Elisabetta author Ratziu, Vlad author Pressiani, Tiziana author D'Alessio, Antonio author Personeni, Nicola author Rimassa, Lorenza author Daly, Ann K author Scheiner, Bernhard author Pomej, Katharina author Kirstein, Martha M author Vogel, Arndt author Peck-Radosavljevic, Markus author Hucke, Florian author Finkelmeier, Fabian author Waidmann, Oliver author Trojan, Jörg author Schulze, Kornelius author Wege, Henning author Koch, Sandra author Weinmann, Arndt author Bueter, Marco author Rössler, Fabian author Siebenhüner, Alexander author De Dosso, Sara author Mallm, Jan-Philipp author Umansky, Viktor author Jugold, Manfred author Luedde, Tom author Schietinger, Andrea author Schirmacher, Peter author Emu, Brinda author Augustin, Hellmut G author Billeter, Adrian author Müller-Stich, Beat author Kikuchi, Hiroto author Duda, Dan G author Kütting, Fabian author Waldschmidt, Dirk-Thomas author Ebert, Matthias Philip author Rahbari, Nuh author Mei, Henrik E author Schulz, Axel Ronald author Ringelhan, Marc author Malek, Nisar author Spahn, Stephan author Bitzer, Michael author Ruiz de Galarreta, Marina author Lujambio, Amaia author Dufour, Jean-Francois author Marron, Thomas U author Kaseb, Ahmed author Kudo, Masatoshi author Huang, Yi-Hsiang author Djouder, Nabil author Wolter, Katharina author Zender, Lars author Marche, Parice N author Decaens, Thomas author Pinato, David J author Rad, Roland author Mertens, Joachim C author Weber, Achim author Unger, Kristian author Meissner, Felix author Roth, Susanne author Jilkova, Zuzana Macek author Claassen, Manfred author Anstee, Quentin M author Amit, Ido author Knolle, Percy author Becher, Burkhard author Llovet, Josep M author Heikenwalder, Mathias author 2021-04 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. Nature . 2021;592(7854):450-456. 10.1038/s41586-021-03362-0 1476-4687 Nature 33762733 http://hdl.handle.net/20.500.12105/17669 NASH limits anti-tumour surveillance in immunotherapy-treated HCC.