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)
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 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 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 Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen
51 UGA - Université Grenoble Alpes
52 IAB - Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble)
53 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
54 Hammersmith Hospital NHS Imperial College Healthcare
55 UPO - Università degli Studi del Piemonte Orientale - Amedeo Avogadro
56 UB - Universitat de Barcelona
57 ICREA - Institució Catalana de Recerca i Estudis Avançats = Catalan Institution for Research and Advanced Studies
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 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 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 Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen
51 UGA - Université Grenoble Alpes
52 IAB - Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble)
53 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
54 Hammersmith Hospital NHS Imperial College Healthcare
55 UPO - Università degli Studi del Piemonte Orientale - Amedeo Avogadro
56 UB - Universitat de Barcelona
57 ICREA - Institució Catalana de Recerca i Estudis Avançats = Catalan Institution for Research and Advanced Studies
Aleksandra Deczkowska
- Fonction : Auteur
- PersonId : 780450
- ORCID : 0000-0003-0844-4346
Indrabahadur Singh
- Fonction : Auteur
- PersonId : 799200
- ORCID : 0000-0002-1474-7928
Vlad Ratziu
- Fonction : Auteur
- PersonId : 762368
- ORCID : 0000-0002-6865-3791
Dan Duda
- Fonction : Auteur
- PersonId : 806026
- ORCID : 0000-0001-7065-8797
Thomas Decaens
- Fonction : Auteur
- PersonId : 757228
- ORCID : 0000-0003-0928-0048
- IdRef : 077283465
Achim Weber
- Fonction : Auteur
- PersonId : 760205
- ORCID : 0000-0003-0073-3637
Ido Amit
- Fonction : Auteur
- PersonId : 779298
- ORCID : 0000-0003-2968-877X
Burkhard Becher
- Fonction : Auteur
- PersonId : 784536
- ORCID : 0000-0002-1541-7867
- IdRef : 181357747
Résumé
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.
Origine : Publication financée par une institution