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NASH limits anti-tumour surveillance in immunotherapy-treated HCC |
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Nature. 2021 Mar 24. doi: 10.1038/s41586-021-03362-0. Online ahead of print.
Dominik Pfister 1 2, Nicolás Gonzalo Núñez 3, Roser Pinyol 4, Olivier Govaere 5, Matthias Pinter 6 7, Marta Szydlowska 1, Revant Gupta 8 9, Mengjie Qiu 10, Aleksandra Deczkowska 11, Assaf Weiner 11, Florian Müller 1, Ankit Sinha 12 13, Ekaterina Friebel 3, Thomas Engleitner 14 15 16, Daniela Lenggenhager 17, Anja Moncsek 18, Danijela Heide 1, Kristin Stirm 1, Jan Kosla 1, Eleni Kotsiliti 1, Valentina Leone 1 19, Michael Dudek 20, Suhail Yousuf 10, Donato Inverso 21 22, Indrabahadur Singh 1 23, Ana Teijeiro 24, Florian Castet 4, Carla Montironi 4, Philipp K Haber 25, Dina Tiniakos 5 26, Pierre Bedossa 5, Simon Cockell 27, Ramy Younes 5 28, Michele Vacca 29, Fabio Marra 30, Jörn M Schattenberg 31, Michael Allison 32, Elisabetta Bugianesi 28, Vlad Ratziu 33, Tiziana Pressiani 34, Antonio D'Alessio 34, Nicola Personeni 34 35, Lorenza Rimassa 34 35, Ann K Daly 5, Bernhard Scheiner 6 7, Katharina Pomej 6 7, Martha M Kirstein 36 37, Arndt Vogel 36, Markus Peck-Radosavljevic 38, Florian Hucke 38, Fabian Finkelmeier 39, Oliver Waidmann 39, Jörg Trojan 39, Kornelius Schulze 40, Henning Wege 40, Sandra Koch 41, Arndt Weinmann 41, Marco Bueter 42, Fabian Rössler 42, Alexander Siebenhüner 43, Sara De Dosso 44, Jan-Philipp Mallm 45, Viktor Umansky 46 47, Manfred Jugold 48, Tom Luedde 49, Andrea Schietinger 50 51, Peter Schirmacher 52, Brinda Emu 1, Hellmut G Augustin 21 22, Adrian Billeter 53, Beat Müller-Stich 53, Hiroto Kikuchi 54, Dan G Duda 54, Fabian Kütting 55, Dirk-Thomas Waldschmidt 55, Matthias Philip Ebert 56, Nuh Rahbari 57, Henrik E Mei 58, Axel Ronald Schulz 58, Marc Ringelhan 59 60 61, Nisar Malek 62, Stephan Spahn 62, Michael Bitzer 62, Marina Ruiz de Galarreta 25 63, Amaia Lujambio 25 63 64, Jean-Francois Dufour 65 66, Thomas U Marron 25 67, Ahmed Kaseb 68, Masatoshi Kudo 69, Yi-Hsiang Huang 70 71, Nabil Djouder 24, Katharina Wolter 72 73, Lars Zender 72 73 74, Parice N Marche 75 76, Thomas Decaens 75 76 77, David J Pinato 78 79, Roland Rad 14 15 16, Joachim C Mertens 18, Achim Weber 17 80, Kristian Unger 19, Felix Meissner 12, Susanne Roth 10, Zuzana Macek Jilkova 75 76 78, Manfred Claassen 8 9, Quentin M Anstee 5 81, Ido Amit 11, Percy Knolle 20, Burkhard Becher 3, Josep M Llovet 82 83 84, Mathias Heikenwalder 85
Affiliations collapse
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Author information
- 1Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- 2Liver Disease Research, Global Drug Discovery, Novo Nordisk A/S, Malov, Denmark.
- 3Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
- 4Liver Cancer Translational Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, Liver Unit, Universitat de Barcelona, Barcelona, Spain.
- 5Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle, UK.
- 6Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
- 7Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria.
- 8Internal Medicine I, University Hospital Tübingen, Faculty of Medicine, University of Tübingen, Tübingen, Germany.
- 9Department of Computer Science, University of Tübingen, Tübingen, Germany.
- 10Department of General, Visceral and Transplantation Surgery, Universitätsklinikum Heidelberg, Heidelberg, Germany.
- 11Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
- 12Experimental Systems Immunology Laboratory, Max-Planck Institute of Biochemistry, Munich, Germany.
- 13Institute of Translational Cancer Research and Experimental Cancer Therapy, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
- 14Center for Translational Cancer Research (TranslaTUM), Technical University Munich, Munich, Germany.
- 15Department of Medicine II, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.
- 16German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Munich, Germany.
- 17Department of Pathology and Molecular Pathology, University and University Hospital Zurich, Zurich, Switzerland.
- 18Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
- 19Research Unit of Radiation Cytogenetics, Helmholtz Zentrum Munich, Munich, Germany.
- 20Institute of Molecular Immunology and Experimental Oncology, Technical University Munich, Munich, Germany.
- 21Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany.
- 22European Center of Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
- 23Emmy Noether Research Group Epigenetic Machineries and Cancer, Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- 24Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Spanish National Cancer Research Centre, CNIO, Madrid, Spain.
- 25Mount Sinai Liver Cancer Program, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- 26Department of Pathology, Aretaeion Hospita, National and Kapodistrian University of Athens, Athens, Greece.
- 27Bioinformatics Support Unit, Faculty of Medical Sciences, Newcastle University, Newcastle, UK.
- 28Department of Medical Sciences, Division of Gastro-Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, Turn, Italy.
- 29University of Cambridge Metabolic Research Laboratories, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
- 30Dipartimento di Medicina Sperimentale e Clinica, University of Florence, Florence, Italy.
- 31Metabolic Liver Research Program, I. Department of Medicine, University Medical Center Mainz, Mainz, Germany.
- 32Liver Unit, Department of Medicine, Cambridge Biomedical Research Centre, Cambridge University NHS Foundation Trust, Cambridge, UK.
- 33Assistance Publique-Hôpitaux de Paris, Hôpital Beaujon, University Paris-Diderot, Paris, France.
- 34Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center-IRCCS, Milan, Italy.
- 35Department of Biomedical Sciences, Humanitas University, Milan, Italy.
- 36Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
- 37University Medical Center Schleswig-Holstein, Schleswig-Holstein, Germany.
- 38Department of Internal Medicine and Gastroenterology (IMuG), Hepatology, Endocrinology, Rheumatology and Nephrology including Centralized Emergency Department (ZAE), Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria.
- 39Department of Gastroenterology, Hepatology and Endocrinology, University Hospital Frankfurt, Frankfurt, Germany.
- 40Department of Internal Medicine, Gastroenterology & Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- 41Department of Internal Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
- 42Department of Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland.
- 43Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
- 44Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
- 45Division of Chromatin Networks, German Cancer Research Center (DKFZ) and Bioquant, Heidelberg, Germany.
- 46Clinical Cooperation Unit Dermato-Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- 47Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Heidelberg, Germany.
- 48Core Facility Small Animal Imaging, German Cancer Research Center Heidelberg, Heidelberg, Germany.
- 49Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
- 50Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- 51Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.
- 52Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
- 53Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.
- 54Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA.
- 55Department of Gastroenterology and Hepatology, University of Cologne, Cologne, Germany.
- 56Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
- 57Department of Surgery at University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
- 58Mass Cytometry Lab, Deutsches Rheumaforschungszentrum Berlin, a Leibniz Institute, Berlin, Germany.
- 59Institute of Virology, Technical University Munich/Helmholtz Zentrum Munich, Munich, Germany.
- 60Department of Internal Medicine II, University Hospital rechts der Isar, Technical University Munich, Munich, Germany.
- 61German Center for Infection Research (DZIF), partner site Munich, Munich, Germany.
- 62Medical University Hospital Department of Internal Medicine I, Tübingen, Germany.
- 63Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- 64The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- 65University Clinic for Visceral Surgery and Medicine, Inselspital, Bern, Switzerland.
- 66Hepatology, Department of Biomedical Research, University of Bern, Bern, Switzerland.
- 67Department of Medicine, Division of Hematology/Oncology, Tisch Cancer Institute, Mount Sinai Hospital, New York, NY, USA.
- 68Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- 69Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-, Sayama, Japan.
- 70Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
- 71Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan.
- 72Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tübingen, Tübingen, Germany.
- 73Cluster of Excellence 'Image Guided and Functionally Instructed Tumor Therapies' (iFIT), Eberhard-Karls University of Tübingen, Tübingen, Germany.
- 74German Consortium for Translational Cancer Research (DKTK), Partner Site Tübingen, German Cancer Research Center (DKFZ), Tübingen, Germany.
- 75Université Grenoble Alpes, Grenoble, France.
- 76Institute for Advanced Biosciences, Research Center UGA/Inserm U 1209/CNRS 5309, Grenoble, France.
- 77Service d'hépato-gastroentérologie, Pôle Digidune, CHU Grenoble Alpes, Grenoble, France.
- 78Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK.
- 79Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.
- 80Institute of Molecular Cancer Research (IMCR), University of Zurich, Zurich, Switzerland.
- 81Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Trust, Newcastle, UK.
- 82Liver Cancer Translational Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, Liver Unit, Universitat de Barcelona, Barcelona, Spain. jmllovet@clinic.cat.
- 83Mount Sinai Liver Cancer Program, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA. jmllovet@clinic.cat.
- 84Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. jmllovet@clinic.cat.
- 85Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. m.heikenwaelder@dkfz-heidelberg.de.
Abstract
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, 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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