NASH limits anti-tumour surveillance in immunotherapy-treated HCC
Creators: name: Pfister, Dominik
name: Núñez, Nicolás Gonzalo
name: Pinyol, Roser
name: Govaere, Olivier
name: Pinter, Matthias
name: Szydlowska, Marta
name: Gupta, Revant
name: Qiu, Mengjie
name: Deczkowska, Aleksandra
name: Weiner, Assaf
name: Müller, Florian
name: Sinha, Ankit
name: Friebel, Ekaterina
name: Engleitner, Thomas
name: Lenggenhager, Daniela
name: Moncsek, Anja
name: Heide, Danijela
name: Stirm, Kristin
name: Kosla, Jan
name: Kotsiliti, Eleni
name: Leone, Valentina
name: Dudek, Michael
name: Yousuf, Suhail
name: Inverso, Donato
name: Singh, Indrabahadur
name: Teijeiro, Ana
name: Castet, Florian
name: Montironi, Carla
name: Haber, Philipp K.
name: Tiniakos, Dina
name: Bedossa, Pierre
name: Cockell, Simon
name: Younes, Ramy
name: Vacca, Michele
name: Marra, Fabio
name: Schattenberg, Jörn M.
name: Allison, Michael
name: Bugianesi, Elisabetta
name: Ratziu, Vlad
name: Pressiani, Tiziana
name: D’Alessio, Antonio
name: Personeni, Nicola
name: Rimassa, Lorenza
name: Daly, Ann K.
name: Scheiner, Bernhard
name: Pomej, Katharina
name: Kirstein, Martha M.
name: Vogel, Arndt
name: Peck-Radosavljevic, Markus
name: Hucke, Florian
name: Finkelmeier, Fabian
name: Waidmann, Oliver
name: Trojan, Jörg
name: Schulze, Kornelius
name: Wege, Henning
name: Koch, Sandra
name: Weinmann, Arndt
name: Bueter, Marco
name: Rössler, Fabian
name: Siebenhüner, Alexander
name: De Dosso, Sara
name: Mallm, Jan-Philipp
name: Umansky, Viktor
name: Jugold, Manfred
name: Luedde, Tom
name: Schietinger, Andrea
name: Schirmacher, Peter
name: Emu, Brinda
name: Augustin, Hellmut G.
name: Billeter, Adrian
name: Müller-Stich, Beat
name: Kikuchi, Hiroto
name: Duda, Dan G.
name: Kütting, Fabian
name: Waldschmidt, Dirk-Thomas
name: Ebert, Matthias Philip
name: Rahbari, Nuh
name: Mei, Henrik E.
name: Schulz, Axel Ronald
name: Ringelhan, Marc
name: Malek, Nisar
name: Spahn, Stephan
name: Bitzer, Michael
name: Ruiz De Galarreta, Marina
name: Lujambio, Amaia
name: Dufour, Jean-Francois
name: Marron, Thomas U.
name: Kaseb, Ahmed
name: Kudo, Masatoshi
name: Huang, Yi-Hsiang
name: Djouder, Nabil
name: Wolter, Katharina
name: Zender, Lars
name: Marche, Parice N.
name: Decaens, Thomas
name: Pinato, David J.
name: Rad, Roland
name: Mertens, Joachim C.
name: Weber, Achim
name: Unger, Kristian
name: Meissner, Felix
name: Roth, Susanne
name: Jilkova, Zuzana Macek
name: Claassen, Manfred
name: Anstee, Quentin M.
name: Amit, Ido
name: Knolle, Percy
name: Becher, Burkhard
name: Llovet, Josep M.
name: Heikenwalder, Mathias
Publisher: name: Apollo - University of Cambridge Repository
Year: 2021
Subjects: Article
/631/67
/631/250/251
/13/1
/13/31
/13/21
/13/2
/13/51
/14/19
/14/32
/14/34
/14/35
/14/63
/59/57
/64/60
article

description: Abstract: 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.