NASH limits anti-tumour surveillance in immunotherapy-treated HCC

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

*Corresponding author for this work
20 Citations (Scopus)


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.

Original languageEnglish
Issue number7854
Pages (from-to)450-456
Number of pages7
Publication statusPublished - 15.04.2021


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