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NASH limits anti-tumour surveillance in immunotherapy-treated HCC.

ABSTRACT: 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.

SUBMITTER: Pfister D

PROVIDER: S-EPMC8046670 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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NASH limits anti-tumour surveillance in immunotherapy-treated HCC.

Pfister Dominik D Núñez Nicolás Gonzalo NG Pinyol Roser R Govaere Olivier O Pinter Matthias M Szydlowska Marta M Gupta Revant R Qiu Mengjie M Deczkowska Aleksandra A Weiner Assaf A Müller Florian F Sinha Ankit A Friebel Ekaterina E Engleitner Thomas T Lenggenhager Daniela D Moncsek Anja A Heide Danijela D Stirm Kristin K Kosla Jan J Kotsiliti Eleni E Leone Valentina V Dudek Michael M Yousuf Suhail S Inverso Donato D Singh Indrabahadur I Teijeiro Ana A Castet Florian F Montironi Carla C Haber Philipp K PK Tiniakos Dina D Bedossa Pierre P Cockell Simon S Younes Ramy R Vacca Michele M Marra Fabio F Schattenberg Jörn M JM Allison Michael M Bugianesi Elisabetta E Ratziu Vlad V Pressiani Tiziana T D'Alessio Antonio A Personeni Nicola N Rimassa Lorenza L Daly Ann K AK Scheiner Bernhard B Pomej Katharina K Kirstein Martha M MM Vogel Arndt A Peck-Radosavljevic Markus M Hucke Florian F Finkelmeier Fabian F Waidmann Oliver O Trojan Jörg J Schulze Kornelius K Wege Henning H Koch Sandra S Weinmann Arndt A Bueter Marco M Rössler Fabian F Siebenhüner Alexander A De Dosso Sara S Mallm Jan-Philipp JP Umansky Viktor V Jugold Manfred M Luedde Tom T Schietinger Andrea A Schirmacher Peter P Emu Brinda B Augustin Hellmut G HG Billeter Adrian A Müller-Stich Beat B Kikuchi Hiroto H Duda Dan G DG Kütting Fabian F Waldschmidt Dirk-Thomas DT Ebert Matthias Philip MP Rahbari Nuh N Mei Henrik E HE Schulz Axel Ronald AR Ringelhan Marc M Malek Nisar N Spahn Stephan S Bitzer Michael M Ruiz de Galarreta Marina M Lujambio Amaia A Dufour Jean-Francois JF Marron Thomas U TU Kaseb Ahmed A Kudo Masatoshi M Huang Yi-Hsiang YH Djouder Nabil N Wolter Katharina K Zender Lars L Marche Parice N PN Decaens Thomas T Pinato David J DJ Rad Roland R Mertens Joachim C JC Weber Achim A Unger Kristian K Meissner Felix F Roth Susanne S Jilkova Zuzana Macek ZM Claassen Manfred M Anstee Quentin M QM Amit Ido I Knolle Percy P Becher Burkhard B Llovet Josep M JM Heikenwalder Mathias M

Nature 20210324 7854

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 ...[more]

PMID: 33762733

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Project description:Hepatocellular carcinoma (HCC) has dismal treatment responses to systemic therapies and is caused by both, viral and non-viral etiologies, including non-alcoholic steatohepatitis (NASH) 1–5. NASH - triggered by high caloric intake and sedentary lifestyle - has become an important driver for HCC development. Immunotherapy has been recently approved for HCC but stratification of responders versus non-responders has remained an unmet need 5–8. Here, we found a progressive accumulation of non-classical activated CD8+PD-1+ T-cells in livers of NASH-affected patients and mice. PD-L1/PD-1-targeted immunotherapy of NASH-induced HCC administered either at cancer-initiation or after cancer-establishment lacked beneficial effects in mice. On the contrary, PD-1-targeted immunotherapy drove hepatic necro-inflammation and increased liver cancer incidence, tumor number, and nodule size. Anti-CD8 or anti-CD8/anti-NK1.1 treatment suppressed liver cancer development, implicating CD8+ T-cells as liver cancer drivers in the context of NASH. In line, PD-1-/- mice challenged with a NASH-inducing diet displayed early-onset of liver cancer. Mechanistically, PD-1-targeted immunotherapy triggered necro-inflammation and a pro-tumorigenic environment in the context of NASH, increasing the abundance of hepatic TOX+CXCR6+ expressing CD8+PD-1+ TNF+ T-cells. Anti-CD8/anti-PD-1 or anti-TNF/anti-PD-1, but not anti-CD4/anti-PD-1 treatment reverted anti-PD1 treatment-related increase of liver inflammation, NASH severity and tumorigenesis. Gene expression profile and increased abundance of murine hepatic CD8+PD-1+ T-cells were corroborated in human CD8+PD-1+ T cells derived from NASH patients. In a meta-analysis of clinical trials testing PD-1-targeting immune checkpoint inhibitors alone (i.e. pembrolizumab) or in combination in 1656 patients with advanced HCC, immunotherapy was not favorable over to control treatment in non-viral- when compared to viral-related HCC. Similarly, in two clinical cohorts tested, patients with NASH-driven HCC had a significantly worse overall survival with PD-1-targeted immunotherapy than HCC patients with other etiologies. Our data identify non-viral etiologies, particularly NASH, as potentially non-responsive in the context of HCC immunotherapy, providing a strong rational basis for patient stratification.

Dataset Information

NASH limits anti-tumour surveillance in immunotherapy-treated HCC.

Publications

NASH limits anti-tumour surveillance in immunotherapy-treated HCC.

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