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NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Dominik Pfister 1, 2 Nicolás Gonzalo Núñez 3 Roser Pinyol 4 Olivier Govaere 5 Matthias Pinter 6 Marta Szydlowska 1 Revant Gupta 7 Mengjie Qiu 8 Aleksandra Deczkowska 9 Assaf Weiner 9 Florian Müller 1 Ankit Sinha 10, 11 Ekaterina Friebel 3 Thomas Engleitner 11, 1 Daniela Lenggenhager 12 Anja Moncsek 13 Danijela Heide 1 Kristin Stirm 1 Jan Kosla 1 Eleni Kotsiliti 1 Valentina Leone 1, 13 Michael Dudek 11 Suhail Yousuf 8 Donato Inverso 1, 14 Indrabahadur Singh 1 Ana Teijeiro 15 Florian Castet 4 Carla Montironi 4 Philipp Haber 16 Dina Tiniakos 5, 17 Pierre Bedossa 5 Simon Cockell 5 Ramy Younes 5, 18 Michele Vacca 19 Fabio Marra 20 Jörn Schattenberg 21 Michael Allison 22 Elisabetta Bugianesi 18 Vlad Ratziu 23, 24 Tiziana Pressiani 25 Antonio D’alessio 25 Nicola Personeni 25, 26 Lorenza Rimassa 25, 26 Ann Daly 5 Bernhard Scheiner 6 Katharina Pomej 6 Martha Kirstein 27, 28 Arndt Vogel 27 Markus Peck-Radosavljevic 29 Florian Hucke 29 Fabian Finkelmeier 30 Oliver Waidmann 30 Jörg Trojan 30 Kornelius Schulze 31 Henning Wege 31 Sandra Koch 21 Arndt Weinmann 21 Marco Bueter 12 Fabian Rössler 12 Alexander Siebenhüner 12 Sara de Dosso 32 Jan-Philipp Mallm 1 Viktor Umansky 1, 14 Manfred Jugold 1 Tom Luedde 33 Andrea Schietinger 34, 35 Peter Schirmacher 36 Brinda Emu 1 Hellmut Augustin 1, 37 Adrian Billeter 36 Beat Müller-Stich 36 Hiroto Kikuchi 38 Dan Duda 38 Fabian Kütting 39 Dirk-Thomas Waldschmidt 39 Matthias Philip Ebert 14 Nuh Rahbari 14 Henrik Mei 40 Axel Ronald Schulz 40 Marc Ringelhan 13, 11, 41 Nisar Malek 42 Stephan Spahn 42 Michael Bitzer 42 Marina Ruiz de Galarreta 16 Amaia Lujambio 16 Jean-Francois Dufour 43, 44 Thomas Marron 16 Ahmed Kaseb 45 Masatoshi Kudo 46 Yi-Hsiang Huang 47, 48 Nabil Djouder 15 Katharina Wolter 49, 50 Lars Zender 49, 50, 1 Parice Marche 51, 52 Thomas Decaens 51, 52, 53 David Pinato 54, 55 Roland Rad 11, 1 Joachim Mertens 12 Achim Weber 12, 3 Kristian Unger 13 Felix Meissner 10 Susanne Roth 8 Zuzana Macek Jilkova 51, 52, 54 Manfred Claassen 7 Quentin Anstee 5, 56 Ido Amit 9 Percy Knolle 11 Burkhard Becher 3 Josep Llovet 56, 16, 57 Mathias Heikenwalder 1
Abstract : 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.
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https://www.hal.inserm.fr/inserm-03348110
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Submitted on : Friday, September 17, 2021 - 5:40:33 PM
Last modification on : Wednesday, September 22, 2021 - 3:22:23 AM

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Dominik Pfister, Nicolás Gonzalo Núñez, Roser Pinyol, Olivier Govaere, Matthias Pinter, et al.. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature, Nature Publishing Group, 2021, 592 (7854), pp.450-456. ⟨10.1038/s41586-021-03362-0⟩. ⟨inserm-03348110⟩

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