Pfister, Dominik ORCID: 0000-0002-0542-2638, Nunez, Nicolas Gonzalo, Pinyol, Roser ORCID: 0000-0002-0288-6314, Govaere, Olivier ORCID: 0000-0002-4426-6930, Pinter, Matthias, Szydlowska, Marta ORCID: 0000-0002-4660-899X, Gupta, Revant ORCID: 0000-0002-0881-5074, Qiu, Mengjie, Deczkowska, Aleksandra, Weiner, Assaf, Mueller, Florian, Sinha, Ankit, Friebel, Ekaterina ORCID: 0000-0003-1419-2376, Engleitner, Thomas, Lenggenhager, Daniela, Moncsek, Anja, Heide, Danijela, Stirm, Kristin, Kosla, Jan, Kotsiliti, Eleni, Leone, Valentina, Dudek, Michael, Yousuf, Suhail, Inverso, Donato, Singh, Indrabahadur ORCID: 0000-0002-1474-7928, Teijeiro, Ana ORCID: 0000-0003-2276-7950, Castet, Florian, Montironi, Carla ORCID: 0000-0002-1453-2193, Haber, Philipp K., Tiniakos, Dina, Bedossa, Pierre, Cockell, Simon, Younes, Ramy, Vacca, Michele ORCID: 0000-0002-1973-224X, Marra, Fabio, Schattenberg, Jorn M., Allison, Michael, Bugianesi, Elisabetta, Ratziu, Vlad, Pressiani, Tiziana, D'Alessio, Antonio ORCID: 0000-0002-9164-3671, Personeni, Nicola, Rimassa, Lorenza ORCID: 0000-0001-9957-3615, Daly, Ann K., Scheiner, Bernhard, Pomej, Katharina, Kirstein, Martha M., Vogel, Arndt ORCID: 0000-0003-0560-5538, Peck-Radosavljevic, Markus, Hucke, Florian, Finkelmeier, Fabian, Waidmann, Oliver, Trojan, Jorg, Schulze, Kornelius, Wege, Henning, Koch, Sandra, Weinmann, Arndt ORCID: 0000-0003-1198-1716, Bueter, Marco, Rossler, Fabian, Siebenhuner, Alexander, De Dosso, Sara, Mallm, Jan-Philipp, Umansky, Viktor, Jugold, Manfred, Luedde, Tom, Schietinger, Andrea, Schirmacher, Peter, Emu, Brinda, Augustin, Hellmut G., Billeter, Adrian, Mueller-Stich, Beat, Kikuchi, Hiroto, Duda, Dan G., Kutting, Fabian, Waldschmidt, Dirk-Thomas, Ebert, Matthias Philip, Rahbari, Nuh, Mei, Henrik E., Schulz, Axel Ronald, Ringelhan, Marc ORCID: 0000-0003-3131-5657, Malek, Nisar, Spahn, Stephan, Bitzer, Michael, Ruiz de Galarreta, Marina, Lujambio, Amaia, Dufour, Jean-Francois, Marron, Thomas U., Kaseb, Ahmed, Kudo, Masatoshi, Huang, Yi-Hsiang, Djouder, Nabil, Wolter, Katharina, Zender, Lars, Marche, Parice N., Decaens, Thomas, Pinato, David J., Rad, Roland, Mertens, Joachim C., Weber, Achim, Unger, Kristian, Meissner, Felix ORCID: 0000-0003-1000-7989, Roth, Susanne, Jilkova, Zuzana Macek, Claassen, Manfred, Anstee, Quentin M. ORCID: 0000-0002-9518-0088, Amit, Ido, Knolle, Percy, Becher, Burkhard, Llovet, Josep M. and Heikenwalder, Mathias (2021). NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature, 592 (7854). S. 450 - 457. BERLIN: NATURE PORTFOLIO. ISSN 1476-4687

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Pfister, DominikUNSPECIFIEDorcid.org/0000-0002-0542-2638UNSPECIFIED
Nunez, Nicolas GonzaloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pinyol, RoserUNSPECIFIEDorcid.org/0000-0002-0288-6314UNSPECIFIED
Govaere, OlivierUNSPECIFIEDorcid.org/0000-0002-4426-6930UNSPECIFIED
Pinter, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Szydlowska, MartaUNSPECIFIEDorcid.org/0000-0002-4660-899XUNSPECIFIED
Gupta, RevantUNSPECIFIEDorcid.org/0000-0002-0881-5074UNSPECIFIED
Qiu, MengjieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deczkowska, AleksandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weiner, AssafUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sinha, AnkitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Friebel, EkaterinaUNSPECIFIEDorcid.org/0000-0003-1419-2376UNSPECIFIED
Engleitner, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lenggenhager, DanielaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moncsek, AnjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heide, DanijelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stirm, KristinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kosla, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kotsiliti, EleniUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leone, ValentinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dudek, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yousuf, SuhailUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Inverso, DonatoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Singh, IndrabahadurUNSPECIFIEDorcid.org/0000-0002-1474-7928UNSPECIFIED
Teijeiro, AnaUNSPECIFIEDorcid.org/0000-0003-2276-7950UNSPECIFIED
Castet, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Montironi, CarlaUNSPECIFIEDorcid.org/0000-0002-1453-2193UNSPECIFIED
Haber, Philipp K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tiniakos, DinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bedossa, PierreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cockell, SimonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Younes, RamyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vacca, MicheleUNSPECIFIEDorcid.org/0000-0002-1973-224XUNSPECIFIED
Marra, FabioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schattenberg, Jorn M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Allison, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bugianesi, ElisabettaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ratziu, VladUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pressiani, TizianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
D'Alessio, AntonioUNSPECIFIEDorcid.org/0000-0002-9164-3671UNSPECIFIED
Personeni, NicolaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rimassa, LorenzaUNSPECIFIEDorcid.org/0000-0001-9957-3615UNSPECIFIED
Daly, Ann K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheiner, BernhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pomej, KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kirstein, Martha M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vogel, ArndtUNSPECIFIEDorcid.org/0000-0003-0560-5538UNSPECIFIED
Peck-Radosavljevic, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hucke, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Finkelmeier, FabianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Waidmann, OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trojan, JorgUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulze, KorneliusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wege, HenningUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koch, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weinmann, ArndtUNSPECIFIEDorcid.org/0000-0003-1198-1716UNSPECIFIED
Bueter, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rossler, FabianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Siebenhuner, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Dosso, SaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mallm, Jan-PhilippUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Umansky, ViktorUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jugold, ManfredUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Luedde, TomUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schietinger, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schirmacher, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Emu, BrindaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Augustin, Hellmut G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Billeter, AdrianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller-Stich, BeatUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kikuchi, HirotoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Duda, Dan G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kutting, FabianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Waldschmidt, Dirk-ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ebert, Matthias PhilipUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rahbari, NuhUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mei, Henrik E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulz, Axel RonaldUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ringelhan, MarcUNSPECIFIEDorcid.org/0000-0003-3131-5657UNSPECIFIED
Malek, NisarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spahn, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bitzer, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ruiz de Galarreta, MarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lujambio, AmaiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dufour, Jean-FrancoisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marron, Thomas U.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kaseb, AhmedUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kudo, MasatoshiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huang, Yi-HsiangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Djouder, NabilUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolter, KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zender, LarsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marche, Parice N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Decaens, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pinato, David J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rad, RolandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mertens, Joachim C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weber, AchimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Unger, KristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meissner, FelixUNSPECIFIEDorcid.org/0000-0003-1000-7989UNSPECIFIED
Roth, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jilkova, Zuzana MacekUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Claassen, ManfredUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Anstee, Quentin M.UNSPECIFIEDorcid.org/0000-0002-9518-0088UNSPECIFIED
Amit, IdoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knolle, PercyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becher, BurkhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Llovet, Josep M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heikenwalder, MathiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-608251
DOI: 10.1038/s41586-021-03362-0
Journal or Publication Title: Nature
Volume: 592
Number: 7854
Page Range: S. 450 - 457
Date: 2021
Publisher: NATURE PORTFOLIO
Place of Publication: BERLIN
ISSN: 1476-4687
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ADVANCED HEPATOCELLULAR-CARCINOMA; LIVER-CANCER; NONALCOHOLIC STEATOHEPATITIS; PHASE-III; R PACKAGE; T-CELLS; RNA-SEQ; NAFLDMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60825

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