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Journal Articles Nature Year : 2021

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, 7) , Lars Zender (49, 7, 1) , Parice Marche (50, 51) , Thomas Decaens (50, 51, 52) , David Pinato (53, 54) , Roland Rad (11, 1) , Joachim Mertens (12) , Achim Weber (12, 3) , Kristian Unger (13) , Felix Meissner (10) , Susanne Roth (8) , Zuzana Macek Jilkova (50, 51, 53) , Manfred Claassen (7) , Quentin Anstee (5, 55) , Ido Amit (9) , Percy Knolle (11) , Burkhard Becher (3) , Josep Llovet (55, 16, 56) , Mathias Heikenwalder (1)
1 DKFZ - German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg]
2 Novo Nordisk A/S [Maløv, Denmark]
3 UZH - Universität Zürich [Zürich] = University of Zurich
4 IDIBAPS - Institut d'Investigacions Biomèdiques August Pi i Sunyer
5 Newcastle University [Newcastle]
6 Medizinische Universität Wien = Medical University of Vienna
7 Eberhard Karls Universität Tübingen = University of Tübingen
8 UniversitätsKlinikum Heidelberg
9 Weizmann Institute of Science [Rehovot, Israël]
10 MPIB - Max-Planck-Institut für Biochemie = Max Planck Institute of Biochemistry
11 TUM - Technische Universität Munchen - Technical University Munich - Université Technique de Munich
12 University hospital of Zurich [Zurich]
13 HMGU - Helmholtz Zentrum München = German Research Center for Environmental Health
14 Universität Heidelberg [Heidelberg] = Heidelberg University
15 CNIO - Spanish National Cancer Research Center
16 MSSM - Icahn School of Medicine at Mount Sinai [New York]
17 NKUA - National and Kapodistrian University of Athens
18 UNITO - Università degli studi di Torino = University of Turin
19 Addenbrooke's Hospital
20 UniFI - Università degli Studi di Firenze = University of Florence = Université de Florence
21 University Medical Center [Mainz]
22 CUH - Cambridge University Hospitals - NHS
23 Hôpital Beaujon [AP-HP]
24 UPD7 - Université Paris Diderot - Paris 7
25 IRCCS Milan - Istituto Clinico Humanitas [Milan]
26 Hunimed - Humanitas University [Milan]
27 MHH - Medizinische Hochschule Hannover = Hannover Medical School
28 UKSH - University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein
29 Klinikum Klagenfurt am Wörthersee
30 Universitätsklinikum Frankfurt
31 UKE - Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg]
32 IOSI - Oncology Institute of Southern Switzerland
33 Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf]
34 Memorial Sloane Kettering Cancer Center [New York]
35 Weill Medical College of Cornell University [New York]
36 Heidelberg University Hospital [Heidelberg]
37 University Hospital Mannheim | Universitätsmedizin Mannheim
38 Massachusetts General Hospital [Boston]
39 University of Cologne
40 DRFZ - Deutsches Rheuma-ForschungsZentrum
41 DZIF - German Center for Infection Research, Partnersite Munich
42 University Medical Center [Tubingen, Germany]
43 Inselspital Bern
44 UNIBE - Universität Bern / University of Bern
45 The University of Texas M.D. Anderson Cancer Center [Houston]
46 Kindai University
47 NYMU - National Yang Ming University
48 Taipei Veterans General Hospital [Taiwan]
49 Universitätsklinikum Tübingen - University Hospital of Tübingen
50 UGA - Université Grenoble Alpes
51 IAB - Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble)
52 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
53 Hammersmith Hospital NHS Imperial College Healthcare
54 UPO - Università degli Studi del Piemonte Orientale - Amedeo Avogadro
55 UB - Universitat de Barcelona
56 ICREA - Institució Catalana de Recerca i Estudis Avançats = Catalan Institution for Research and Advanced Studies
Dan Duda
Masatoshi Kudo

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.

Domains

Immunology Cancer
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Dates and versions

inserm-03348110 , version 1 (17-09-2021)

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Cite

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

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