Details

Autor(en) / Beteiligte

• Pfister, Dominik
• Núñez, Nicolás Gonzalo
• Govaere, Olivier
• Pinter, Matthias
• Szydlowska, Marta
• 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
• Marra, Fabio
• Schattenberg, Jörn M.
• Allison, Michael
• Bugianesi, Elisabetta
• Ratziu, Vlad
• D’Alessio, Antonio
• Personeni, Nicola
• Rimassa, Lorenza
• Daly, Ann K.
• Scheiner, Bernhard
• Pomej, Katharina
• Kirstein, Martha M.
• Peck-Radosavljevic, Markus
• Hucke, Florian
• Finkelmeier, Fabian
• Trojan, Jörg
• Schulze, Kornelius
• Wege, Henning
• Koch, Sandra
• Weinmann, Arndt
• Bueter, Marco
• Rössler, Fabian
• Siebenhüner, Alexander
• 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.
• Waldschmidt, Dirk-Thomas
• 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
• 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

Titel

NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Ist Teil von

• Nature (London), 2021-04, Vol.592 (7854), p.450-456

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2021

Quelle

MEDLINE

Beschreibungen/Notizen

• Hepatocellular carcinoma (HCC) can have viral or non-viral causes 1 – 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 need 6 , 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. In hepatocellular carcinoma driven by non-alcoholic steatohepatitis, aberrant T cell activation and impaired immune surveillance seem to make hepatocellular carcinoma less responsive to anti-PD1 or anti-PDL1 immunotherapy.