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Pfister, D.* ; Núñez, N.G.* ; Pinyol, R.* ; Govaere, O.* ; Pinter, M.* ; Szydlowska, M.* ; Gupta, R.* ; Qiu, M.* ; Deczkowska, A.* ; Weiner, A.* ; Müller, F.* ; Sinha, A.* ; Friebel, E.* ; Engleitner, T.* ; Lenggenhager, D.* ; Moncsek, A.* ; Heide, D.* ; Stirm, K.* ; Kosla, J.* ; Kotsiliti, E.* ; Leone, V. ; Dudek, M.* ; Yousuf, S.* ; Inverso, D.* ; Singh, I.* ; Teijeiro, A.* ; Castet, F.* ; Montironi, C.* ; Haber, P.K.* ; Tiniakos, D.* ; Bedossa, P.* ; Cockell, S.* ; Younes, R.* ; Vacca, M.* ; Marra, F.* ; Schattenberg, J.M.* ; Allison, M.* ; Bugianesi, E.* ; Ratziu, V.* ; Pressiani, T.* ; D'Alessio, A.* ; Personeni, N.* ; Rimassa, L.* ; Daly, A.K.* ; Scheiner, B.* ; Pomej, K.* ; Kirstein, M.M.* ; Vogel, A.* ; Peck-Radosavljevic, M.* ; Hucke, F.* ; Finkelmeier, F.* ; Waidmann, O.* ; Trojan, J.* ; Schulze, K.* ; Wege, H.* ; Koch, S.* ; Weinmann, A.* ; Bueter, M.* ; Rössler, F.* ; Siebenhüner, A.* ; Dosso, S.* ; Mallm, J.P.* ; Umansky, V.* ; Jugold, M.* ; Luedde, T.* ; Schietinger, A.* ; Schirmacher, P.* ; Emu, B.* ; Augustin, H.G.* ; Billeter, A.T.* ; Müller-Stich, B.* ; Kikuchi, H.* ; Duda, D.G.* ; Kütting, F.* ; Waldschmidt, D.T.* ; Ebert, M.P.* ; Rahbari, N.* ; Mei, H.E.* ; Schulz, A.R.* ; Ringelhan, M. ; Malek, N.* ; Spahn, S.* ; Bitzer, M.* ; Ruiz de Galarreta, M.* ; Lujambio, A.* ; Dufour, J.F.* ; Marron, T.U.* ; Kaseb, A.* ; Kudo, M.* ; Huang, Y.H.* ; Djouder, N.* ; Wolter, K.* ; Zender, L.* ; Marche, P.N.* ; Decaens, T.* ; Pinato, D.J.* ; Rad, R.* ; Mertens, J.C.* ; Weber, A.* ; Unger, K. ; Meissner, F.* ; Roth, S.* ; Jilkova, Z.M.* ; Claassen, M.* ; Anstee, Q.M.* ; Amit, I.* ; Knolle, P.* ; Becher, B.* ; Llovet, J.M.* ; Heikenwalder, M.*

NASH limits anti-tumour surveillance in immunotherapy-treated HCC.

Nature 592, 450–456 (2021)
Publ. Version/Full Text DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Advanced Hepatocellular-carcinoma; Liver-cancer; Nonalcoholic Steatohepatitis; Phase-iii; R Package; T-cells; Rna-seq; Nafld
ISSN (print) / ISBN 0028-0836
e-ISSN 1476-4687
Journal Nature
Quellenangaben Volume: 592, Issue: 7854, Pages: 450–456 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Research Unit Radiation Cytogenetics (ZYTO)
Institute of Virology (VIRO)
Grants 'Deutsche Forschungsgemeinschaft' (DFG)
Rio Hortega grant from the ISCIII
HEPCAR
Generalitat de Catalunya/AGAUR
Spanish National Health Institute
Samuel Waxman Cancer Research Foundation
Tisch Cancer Institute
NCI Cancer Center Support Grant
European Social Fund
AECC
Swiss National Science Foundation (SNF)
German Research Foundation
Helmholtz-Gemeinschaft, Zukunftsthema 'Immunology and Inflammation'
German-Israeli Cooperation in Cancer Research (DKFZ-MOST)
Deutsche Krebshilfe projects
Research Foundation Flanders (FWO)
Wilhelm Sander-Stiftung
ERC Consolidator grant (HepatoMetaboPath)
US Department of Defense
European Commission (EC)/Horizon 2020 Program (HEPCAR)
Thompson Family Foundation
European Research Council consolidator grant (ERC-COG)
HHMI international scholar award
Chan Zuckerberg Initiative (CZI)
Newcastle NIHR Biomedical Research Centre
LITMUS (Liver Investigation: Testing Marker Utility in Steatohepatitis) consortium - Innovative Medicines Initiative (IMI2) Program of the European Union
EPoS (Elucidating Pathways of Steatohepatitis) consortium - Horizon 2020 Framework Program of the European Union
EMBO LT fellowship
MRA established investigator award
Israel Science Foundation
Ernest and Bonnie Beutler Research Program for Excellence in Genomic Medicine
Fundacion Cientifica de la Asociacion Espanola Contra el Cancer (HUNTER)
Fondazione AIRC
Cancer Research UK
SCA award of the Wolfson Foundation
Adelis Foundation
NeuroMac DFG/Transregional Collaborative Research Center grant
Helen and Martin Kimmel award for innovative investigation
'Deutsche Forschungsgemeinschaft' (DFG, Bonn Germany) through Emmy Noether program
Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ)
360372040
BMBF
Helmholtz Future topic Inflammation and Immunology
Dangel Stiftung
Bangerter-Rhyner Stiftung
Stiftung zur Krebsbekampfung
Norwegian PSC Research Center
Canica Holding Research Grant
SNF Project Grant
International Progressive MS Alliance/NMSS
National Cancer Institute
Rainer Hoenig Stiftung
SFBTR1335
314905040
SFB/TR 209
272983813
SFBTR179
SFB 1335
CW+
Horizon 2020 grant (Hepcar)
University Research Priority Program (URPP) postdoctoral fellowship
Swiss Cancer League
DFG
Swiss Foundation against Liver Cancer
Swiss National Foundation
German Cancer Aid
Westminster Medical School Research Trust
ASCO/Conquer Cancer Foundation Global Oncology Young Investigator Award 2019
Wellcome Trust Strategic Fund
Elke-Kroner-Fresenius foundation
Deutsche Forschungsgemeinschaft
Swiss National Science Foundation
German Cancer Research Center (DKTK)
European Research Council (CholangioConcept)
Landesstiftung Baden-Wuerttemberg
DFG under Germany's excellence strategy
German Ministry for Education and Research (BMBF)
Israel's Ministry of Science, Technology and Space (MOST)