%0 Journal Article
%A Pfister, Dominik
%A Núñez, Nicolás Gonzalo
%A Pinyol, Roser
%A Govaere, Olivier
%A Pinter, Matthias
%A Szydlowska, Marta
%A Gupta, Revant
%A Qiu, Mengjie
%A Deczkowska, Aleksandra
%A Weiner, Assaf
%A Müller, Florian
%A Sinha, Ankit
%A Friebel, Ekaterina
%A Engleitner, Thomas
%A Lenggenhager, Daniela
%A Moncsek, Anja
%A Heide, Danijela
%A Stirm, Kristin
%A Kosla, Jan
%A Kotsiliti, Eleni
%A Leone, Valentina
%A Dudek, Michael
%A Yousuf, Suhail
%A Inverso, Donato
%A Singh, Indrabahadur
%A Teijeiro, Ana
%A Castet, Florian
%A Montironi, Carla
%A Haber, Philipp K
%A Tiniakos, Dina
%A Bedossa, Pierre
%A Cockell, Simon
%A Younes, Ramy
%A Vacca, Michele
%A Marra, Fabio
%A Schattenberg, Jörn M
%A Allison, Michael
%A Bugianesi, Elisabetta
%A Ratziu, Vlad
%A Pressiani, Tiziana
%A D'Alessio, Antonio
%A Personeni, Nicola
%A Rimassa, Lorenza
%A Daly, Ann K
%A Scheiner, Bernhard
%A Pomej, Katharina
%A Kirstein, Martha M
%A Vogel, Arndt
%A Peck-Radosavljevic, Markus
%A Hucke, Florian
%A Finkelmeier, Fabian
%A Waidmann, Oliver
%A Trojan, Jörg
%A Schulze, Kornelius
%A Wege, Henning
%A Koch, Sandra
%A Weinmann, Arndt
%A Bueter, Marco
%A Rössler, Fabian
%A Siebenhüner, Alexander
%A Dosso, Sara De
%A Mallm, Jan-Philipp
%A Umansky, Viktor
%A Jugold, Manfred
%A Luedde, Tom
%A Schietinger, Andrea
%A Schirmacher, Peter
%A Emu, Brinda
%A Augustin, Hellmut
%A Billeter, Adrian
%A Müller-Stich, Beat
%A Kikuchi, Hiroto
%A Duda, Dan G
%A Kütting, Fabian
%A Waldschmidt, Dirk-Thomas
%A Ebert, Matthias Philip
%A Rahbari, Nuh
%A Mei, Henrik E
%A Schulz, Axel Ronald
%A Ringelhan, Marc
%A Malek, Nisar
%A Spahn, Stephan
%A Bitzer, Michael
%A Ruiz de Galarreta, Marina
%A Lujambio, Amaia
%A Dufour, Jean-Francois
%A Marron, Thomas U
%A Kaseb, Ahmed
%A Kudo, Masatoshi
%A Huang, Yi-Hsiang
%A Djouder, Nabil
%A Wolter, Katharina
%A Zender, Lars
%A Marche, Parice N
%A Decaens, Thomas
%A Pinato, David J
%A Rad, Roland
%A Mertens, Joachim C
%A Weber, Achim
%A Unger, Kristian
%A Meissner, Felix
%A Roth, Susanne
%A Jilkova, Zuzana Macek
%A Claassen, Manfred
%A Anstee, Quentin M
%A Amit, Ido
%A Knolle, Percy
%A Becher, Burkhard
%A Llovet, Josep M
%A Heikenwälder, Mathias
%T NASH limits anti-tumour surveillance in immunotherapy-treated HCC.
%J Nature 
%V 592
%N 7854
%@ 1476-4687
%C London [u.a.]
%I Nature Publ. Group52462
%M DKFZ-2021-00722
%P 450-456
%D 2021
%Z #EA:F180#LA:F180# /592(7854):450-456
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:33762733
%R 10.1038/s41586-021-03362-0
%U https://inrepo02.dkfz.de/record/168182