NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Dominik Pfister, Nicolás Gonzalo Núñez, Roser Pinyol, Olivier Govaere, Matthias Pinter, Marta Szydlowska, Revant Gupta, Mengjie Qiu, Aleksandra Deczkowska, Assaf Weiner, Florian Müller, Ankit Sinha, Ekaterina Friebel, Thomas Engleitner, Daniela Lenggenhager, Anja Moncsek, Danijela Heide, Kristin Stirm, Jan Kosla, Eleni Kotsiliti, Valentina Leone, Michael Dudek, Suhail Yousuf, Donato Inverso, Indrabahadur Singh, Ana Teijeiro, Florian Castet, Carla Montironi, Philipp K. Haber, Dina Tiniakos, Pierre Bedossa, Simon Cockell, Ramy Younes, Michele Vacca, Fabio Marra, Jörn M. Schattenberg, Michael Allison, Elisabetta Bugianesi, Vlad Ratziu, Tiziana Pressiani, Antonio D’Alessio, Nicola Personeni, Lorenza Rimassa, Ann K. Daly, Bernhard Scheiner, Katharina Pomej, Martha M. Kirstein, Arndt Vogel, Markus Peck-Radosavljevic, Florian Hucke, Fabian Finkelmeier, Oliver Waidmann, Jörg Trojan, Kornelius Schulze, Henning Wege, Sandra Koch, Arndt Weinmann, Marco Bueter, Fabian Rössler, Alexander Siebenhüner, Sara De Dosso, Jan-Philipp Mallm, Viktor Umansky, Manfred Jugold, Tom Luedde, Andrea Schietinger, Peter Schirmacher, Brinda Emu, Hellmut G. Augustin, Adrian Billeter, Beat Müller-Stich, Hiroto Kikuchi, Dan G. Duda, Fabian Kütting, Dirk-Thomas Waldschmidt, Matthias Philip Ebert, Nuh Rahbari, Henrik E. Mei, Axel Ronald Schulz, Marc Ringelhan, Nisar Malek, Stephan Spahn, Michael Bitzer, Marina Ruiz de Galarreta, Amaia Lujambio, Jean-Francois Dufour, Thomas U. Marron, Ahmed Kaseb, Masatoshi Kudo, Yi-Hsiang Huang, Nabil Djouder, Katharina Wolter, Lars Zender, Parice N. Marche, Thomas Decaens, David J. Pinato, Roland Rad, Joachim C. Mertens, Achim Weber, Kristian Unger, Felix Meissner, Susanne Roth, Zuzana Macek Jilkova, Manfred Claassen, Quentin M. Anstee, Ido Amit, Percy Knolle, Burkhard Becher, Josep M. Llovet () and Mathias Heikenwalder ()
Additional contact information
Dominik Pfister: German Cancer Research Center (DKFZ)
Nicolás Gonzalo Núñez: University of Zurich
Roser Pinyol: Universitat de Barcelona
Olivier Govaere: Newcastle University
Matthias Pinter: Medical University of Vienna
Marta Szydlowska: German Cancer Research Center (DKFZ)
Revant Gupta: University of Tübingen
Mengjie Qiu: Universitätsklinikum Heidelberg
Aleksandra Deczkowska: Weizmann Institute of Science
Assaf Weiner: Weizmann Institute of Science
Florian Müller: German Cancer Research Center (DKFZ)
Ankit Sinha: Max-Planck Institute of Biochemistry
Ekaterina Friebel: University of Zurich
Thomas Engleitner: Technical University Munich
Daniela Lenggenhager: University and University Hospital Zurich
Anja Moncsek: University Hospital Zurich
Danijela Heide: German Cancer Research Center (DKFZ)
Kristin Stirm: German Cancer Research Center (DKFZ)
Jan Kosla: German Cancer Research Center (DKFZ)
Eleni Kotsiliti: German Cancer Research Center (DKFZ)
Valentina Leone: German Cancer Research Center (DKFZ)
Michael Dudek: Technical University Munich
Suhail Yousuf: Universitätsklinikum Heidelberg
Donato Inverso: German Cancer Research Center (DKFZ-ZMBH Alliance)
Indrabahadur Singh: German Cancer Research Center (DKFZ)
Ana Teijeiro: Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Spanish National Cancer Research Centre, CNIO
Florian Castet: Universitat de Barcelona
Carla Montironi: Universitat de Barcelona
Philipp K. Haber: Icahn School of Medicine at Mount Sinai
Dina Tiniakos: Newcastle University
Pierre Bedossa: Newcastle University
Simon Cockell: Newcastle University
Ramy Younes: Newcastle University
Michele Vacca: University of Cambridge Metabolic Research Laboratories, Wellcome-MRC Institute of Metabolic Science, Addenbrooke’s Hospital
Fabio Marra: University of Florence
Jörn M. Schattenberg: University Medical Center Mainz
Michael Allison: Cambridge University NHS Foundation Trust
Elisabetta Bugianesi: University of Turin
Vlad Ratziu: University Paris-Diderot
Tiziana Pressiani: Humanitas Clinical and Research Center-IRCCS
Antonio D’Alessio: Humanitas Clinical and Research Center-IRCCS
Nicola Personeni: Humanitas Clinical and Research Center-IRCCS
Lorenza Rimassa: Humanitas Clinical and Research Center-IRCCS
Ann K. Daly: Newcastle University
Bernhard Scheiner: Medical University of Vienna
Katharina Pomej: Medical University of Vienna
Martha M. Kirstein: Hepatology and Endocrinology, Hannover Medical School
Arndt Vogel: Hepatology and Endocrinology, Hannover Medical School
Markus Peck-Radosavljevic: Klinikum Klagenfurt am Wörthersee
Florian Hucke: Klinikum Klagenfurt am Wörthersee
Fabian Finkelmeier: University Hospital Frankfurt
Oliver Waidmann: University Hospital Frankfurt
Jörg Trojan: University Hospital Frankfurt
Kornelius Schulze: University Medical Center Hamburg-Eppendorf
Henning Wege: University Medical Center Hamburg-Eppendorf
Sandra Koch: University Medical Center of the Johannes Gutenberg University Mainz
Arndt Weinmann: University Medical Center of the Johannes Gutenberg University Mainz
Marco Bueter: University Hospital Zurich
Fabian Rössler: University Hospital Zurich
Alexander Siebenhüner: University Hospital Zurich and University of Zurich
Sara De Dosso: Oncology Institute of Southern Switzerland
Jan-Philipp Mallm: German Cancer Research Center (DKFZ) and Bioquant
Viktor Umansky: German Cancer Research Center (DKFZ)
Manfred Jugold: German Cancer Research Center Heidelberg
Tom Luedde: Medical Faculty, Heinrich-Heine-University
Andrea Schietinger: Immunology Program, Memorial Sloan Kettering Cancer Center
Peter Schirmacher: University Hospital Heidelberg
Brinda Emu: German Cancer Research Center (DKFZ)
Hellmut G. Augustin: German Cancer Research Center (DKFZ-ZMBH Alliance)
Adrian Billeter: Heidelberg University Hospital
Beat Müller-Stich: Heidelberg University Hospital
Hiroto Kikuchi: Massachusetts General Hospital
Dan G. Duda: Massachusetts General Hospital
Fabian Kütting: University of Cologne
Dirk-Thomas Waldschmidt: University of Cologne
Matthias Philip Ebert: Heidelberg University
Nuh Rahbari: Heidelberg University
Henrik E. Mei: Mass Cytometry Lab, Deutsches Rheumaforschungszentrum Berlin, a Leibniz Institute
Axel Ronald Schulz: Mass Cytometry Lab, Deutsches Rheumaforschungszentrum Berlin, a Leibniz Institute
Marc Ringelhan: Technical University Munich/Helmholtz Zentrum Munich
Nisar Malek: Medical University Hospital Department of Internal Medicine I
Stephan Spahn: Medical University Hospital Department of Internal Medicine I
Michael Bitzer: Medical University Hospital Department of Internal Medicine I
Marina Ruiz de Galarreta: Icahn School of Medicine at Mount Sinai
Amaia Lujambio: Icahn School of Medicine at Mount Sinai
Jean-Francois Dufour: University Clinic for Visceral Surgery and Medicine, Inselspital
Thomas U. Marron: Icahn School of Medicine at Mount Sinai
Ahmed Kaseb: The University of Texas MD Anderson Cancer Center
Masatoshi Kudo: Kindai University Faculty of Medicine, Osaka-
Yi-Hsiang Huang: National Yang-Ming University
Nabil Djouder: Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Spanish National Cancer Research Centre, CNIO
Katharina Wolter: University Hospital Tübingen
Lars Zender: University Hospital Tübingen
Parice N. Marche: Université Grenoble Alpes
Thomas Decaens: Université Grenoble Alpes
David J. Pinato: Hammersmith Hospital
Roland Rad: Technical University Munich
Joachim C. Mertens: University Hospital Zurich
Achim Weber: University and University Hospital Zurich
Kristian Unger: Research Unit of Radiation Cytogenetics, Helmholtz Zentrum Munich
Felix Meissner: Max-Planck Institute of Biochemistry
Susanne Roth: Universitätsklinikum Heidelberg
Zuzana Macek Jilkova: Université Grenoble Alpes
Manfred Claassen: University of Tübingen
Quentin M. Anstee: Newcastle University
Ido Amit: Weizmann Institute of Science
Percy Knolle: Technical University Munich
Burkhard Becher: University of Zurich
Josep M. Llovet: Universitat de Barcelona
Mathias Heikenwalder: German Cancer Research Center (DKFZ)

Nature, 2021, vol. 592, issue 7854, 450-456

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03362-0

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