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

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.