NASH limits anti-tumour surveillance in immunotherapy-treated HCC.

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; Dosso, Sara De; 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     «

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, Phi...     »

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.      «

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 prog...     »