NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Author:

Pfister DominikORCID,Núñez Nicolás GonzaloORCID,Pinyol Roser,Govaere OlivierORCID,Pinter Matthias,Szydlowska MartaORCID,Gupta RevantORCID,Qiu Mengjie,Deczkowska AleksandraORCID,Weiner Assaf,Müller Florian,Sinha Ankit,Friebel EkaterinaORCID,Engleitner Thomas,Lenggenhager DanielaORCID,Moncsek AnjaORCID,Heide Danijela,Stirm Kristin,Kosla Jan,Kotsiliti Eleni,Leone Valentina,Dudek Michael,Yousuf Suhail,Inverso DonatoORCID,Singh Indrabahadur,Teijeiro Ana,Castet Florian,Montironi Carla,Haber Philipp K.,Tiniakos Dina,Bedossa Pierre,Cockell Simon,Younes Ramy,Vacca MicheleORCID,Marra FabioORCID,Schattenberg Jörn M.,Allison MichaelORCID,Bugianesi Elisabetta,Ratziu Vlad,Pressiani Tiziana,D’Alessio AntonioORCID,Personeni NicolaORCID,Rimassa LorenzaORCID,Daly Ann K.,Scheiner Bernhard,Pomej KatharinaORCID,Kirstein Martha M.,Vogel Arndt,Peck-Radosavljevic MarkusORCID,Hucke Florian,Finkelmeier Fabian,Waidmann Oliver,Trojan Jörg,Schulze Kornelius,Wege Henning,Koch Sandra,Weinmann Arndt,Bueter Marco,Rössler Fabian,Siebenhüner Alexander,De Dosso Sara,Mallm Jan-PhilippORCID,Umansky Viktor,Jugold Manfred,Luedde Tom,Schietinger AndreaORCID,Schirmacher Peter,Emu Brinda,Augustin Hellmut G.ORCID,Billeter Adrian,Müller-Stich Beat,Kikuchi HirotoORCID,Duda Dan G.ORCID,Kütting Fabian,Waldschmidt Dirk-Thomas,Ebert Matthias Philip,Rahbari Nuh,Mei Henrik E.ORCID,Schulz Axel RonaldORCID,Ringelhan MarcORCID,Malek Nisar,Spahn Stephan,Bitzer Michael,Ruiz de Galarreta Marina,Lujambio AmaiaORCID,Dufour Jean-FrancoisORCID,Marron Thomas U.,Kaseb Ahmed,Kudo MasatoshiORCID,Huang Yi-Hsiang,Djouder NabilORCID,Wolter Katharina,Zender LarsORCID,Marche Parice N.,Decaens Thomas,Pinato David J.ORCID,Rad RolandORCID,Mertens Joachim C.ORCID,Weber AchimORCID,Unger Kristian,Meissner FelixORCID,Roth Susanne,Jilkova Zuzana Macek,Claassen Manfred,Anstee Quentin M.,Amit IdoORCID,Knolle PercyORCID,Becher BurkhardORCID,Llovet Josep M.ORCID,Heikenwalder MathiasORCID

Abstract

AbstractHepatocellular 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.

Publisher

Springer Science and Business Media LLC

Subject

Multidisciplinary

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