NASH limits anti-tumour surveillance in immunotherapy-treated HCC
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 MedUni Vienna - Medical University of Vienna = Medizinische Universität Wien
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 MSKCC - Memorial Sloan Kettering Cancer Center
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 Universität zu Köln = 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 = Université de Berne
45 MD 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 Tuebingen
50 UGA - Université Grenoble Alpes
51 IAB - Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble)
52 DIMAC - IAB - Dynamique cellulaire, Immunité, Métabolisme & Cancer/Cell Dynamics, Immunity, Metabolism & Cancer
53 CHUGA - CHU de Grenoble-Alpes - 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
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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.
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