TY  - JOUR
AU  - Pfister, Dominik
AU  - Núñez, Nicolás Gonzalo
AU  - Pinyol, Roser
AU  - Govaere, Olivier
AU  - Pinter, Matthias
AU  - Szydlowska, Marta
AU  - Gupta, Revant
AU  - Qiu, Mengjie
AU  - Deczkowska, Aleksandra
AU  - Weiner, Assaf
AU  - Müller, Florian
AU  - Sinha, Ankit
AU  - Friebel, Ekaterina
AU  - Engleitner, Thomas
AU  - Lenggenhager, Daniela
AU  - Moncsek, Anja
AU  - Heide, Danijela
AU  - Stirm, Kristin
AU  - Kosla, Jan
AU  - Kotsiliti, Eleni
AU  - Leone, Valentina
AU  - Dudek, Michael
AU  - Yousuf, Suhail
AU  - Inverso, Donato
AU  - Singh, Indrabahadur
AU  - Teijeiro, Ana
AU  - Castet, Florian
AU  - Montironi, Carla
AU  - Haber, Philipp K
AU  - Tiniakos, Dina
AU  - Bedossa, Pierre
AU  - Cockell, Simon
AU  - Younes, Ramy
AU  - Vacca, Michele
AU  - Marra, Fabio
AU  - Schattenberg, Jörn M
AU  - Allison, Michael
AU  - Bugianesi, Elisabetta
AU  - Ratziu, Vlad
AU  - Pressiani, Tiziana
AU  - D'Alessio, Antonio
AU  - Personeni, Nicola
AU  - Rimassa, Lorenza
AU  - Daly, Ann K
AU  - Scheiner, Bernhard
AU  - Pomej, Katharina
AU  - Kirstein, Martha M
AU  - Vogel, Arndt
AU  - Peck-Radosavljevic, Markus
AU  - Hucke, Florian
AU  - Finkelmeier, Fabian
AU  - Waidmann, Oliver
AU  - Trojan, Jörg
AU  - Schulze, Kornelius
AU  - Wege, Henning
AU  - Koch, Sandra
AU  - Weinmann, Arndt
AU  - Bueter, Marco
AU  - Rössler, Fabian
AU  - Siebenhüner, Alexander
AU  - Dosso, Sara De
AU  - Mallm, Jan-Philipp
AU  - Umansky, Viktor
AU  - Jugold, Manfred
AU  - Luedde, Tom
AU  - Schietinger, Andrea
AU  - Schirmacher, Peter
AU  - Emu, Brinda
AU  - Augustin, Hellmut
AU  - Billeter, Adrian
AU  - Müller-Stich, Beat
AU  - Kikuchi, Hiroto
AU  - Duda, Dan G
AU  - Kütting, Fabian
AU  - Waldschmidt, Dirk-Thomas
AU  - Ebert, Matthias Philip
AU  - Rahbari, Nuh
AU  - Mei, Henrik E
AU  - Schulz, Axel Ronald
AU  - Ringelhan, Marc
AU  - Malek, Nisar
AU  - Spahn, Stephan
AU  - Bitzer, Michael
AU  - Ruiz de Galarreta, Marina
AU  - Lujambio, Amaia
AU  - Dufour, Jean-Francois
AU  - Marron, Thomas U
AU  - Kaseb, Ahmed
AU  - Kudo, Masatoshi
AU  - Huang, Yi-Hsiang
AU  - Djouder, Nabil
AU  - Wolter, Katharina
AU  - Zender, Lars
AU  - Marche, Parice N
AU  - Decaens, Thomas
AU  - Pinato, David J
AU  - Rad, Roland
AU  - Mertens, Joachim C
AU  - Weber, Achim
AU  - Unger, Kristian
AU  - Meissner, Felix
AU  - Roth, Susanne
AU  - Jilkova, Zuzana Macek
AU  - Claassen, Manfred
AU  - Anstee, Quentin M
AU  - Amit, Ido
AU  - Knolle, Percy
AU  - Becher, Burkhard
AU  - Llovet, Josep M
AU  - Heikenwälder, Mathias
TI  - NASH limits anti-tumour surveillance in immunotherapy-treated HCC.
JO  - Nature 
VL  - 592
IS  - 7854
SN  - 1476-4687
CY  - London [u.a.]
PB  - Nature Publ. Group52462
M1  - DKFZ-2021-00722
SP  - 450-456
PY  - 2021
N1  - #EA:F180#LA:F180# /592(7854):450-456
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:33762733
DO  - DOI:10.1038/s41586-021-03362-0
UR  - https://inrepo02.dkfz.de/record/168182
ER  -