2026-05-17T01:44:10Zhttps://repisalud.isciii.es/rest/oai/request
oai:repisalud.isciii.es:20.500.12105/176692024-11-29T14:09:21Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud author Pfister, Dominik author Núñez, Nicolás Gonzalo author Pinyol, Roser author Govaere, Olivier author Pinter, Matthias author Szydlowska, Marta author Gupta, Revant author Qiu, Mengjie author Deczkowska, Aleksandra author Weiner, Assaf author Müller, Florian author Sinha, Ankit author Friebel, Ekaterina author Engleitner, Thomas author Lenggenhager, Daniela author Moncsek, Anja author Heide, Danijela author Stirm, Kristin author Kosla, Jan author Kotsiliti, Eleni author Leone, Valentina author Dudek, Michael author Yousuf, Suhail author Inverso, Donato author Singh, Indrabahadur author Teijeiro, Ana author Castet, Florian author Montironi, Carla author Haber, Philipp K author Tiniakos, Dina author Bedossa, Pierre author Cockell, Simon author Younes, Ramy author Vacca, Michele author Marra, Fabio author Schattenberg, Jörn M author Allison, Michael author Bugianesi, Elisabetta author Ratziu, Vlad author Pressiani, Tiziana author D'Alessio, Antonio author Personeni, Nicola author Rimassa, Lorenza author Daly, Ann K author Scheiner, Bernhard author Pomej, Katharina author Kirstein, Martha M author Vogel, Arndt author Peck-Radosavljevic, Markus author Hucke, Florian author Finkelmeier, Fabian author Waidmann, Oliver author Trojan, Jörg author Schulze, Kornelius author Wege, Henning author Koch, Sandra author Weinmann, Arndt author Bueter, Marco author Rössler, Fabian author Siebenhüner, Alexander author De Dosso, Sara author Mallm, Jan-Philipp author Umansky, Viktor author Jugold, Manfred author Luedde, Tom author Schietinger, Andrea author Schirmacher, Peter author Emu, Brinda author Augustin, Hellmut G author Billeter, Adrian author Müller-Stich, Beat author Kikuchi, Hiroto author Duda, Dan G author Kütting, Fabian author Waldschmidt, Dirk-Thomas author Ebert, Matthias Philip author Rahbari, Nuh author Mei, Henrik E author Schulz, Axel Ronald author Ringelhan, Marc author Malek, Nisar author Spahn, Stephan author Bitzer, Michael author Ruiz de Galarreta, Marina author Lujambio, Amaia author Dufour, Jean-Francois author Marron, Thomas U author Kaseb, Ahmed author Kudo, Masatoshi author Huang, Yi-Hsiang author Djouder, Nabil author Wolter, Katharina author Zender, Lars author Marche, Parice N author Decaens, Thomas author Pinato, David J author Rad, Roland author Mertens, Joachim C author Weber, Achim author Unger, Kristian author Meissner, Felix author Roth, Susanne author Jilkova, Zuzana Macek author Claassen, Manfred author Anstee, Quentin M author Amit, Ido author Knolle, Percy author Becher, Burkhard author Llovet, Josep M author Heikenwalder, Mathias funder Deutsche Forschungsgemeinschaft (Alemania) funder European Molecular Biology Organization funder Unión Europea. Comisión Europea. H2020 funder Howard Hughes Medical Institute funder Israel Science Foundation funder Cancer Research UK (Reino Unido) funder Asociación Española Contra el Cáncer funder United States Department of Health and Human Services funder Government of Catalonia (España) funder Instituto de Salud Carlos III 2024-02-08T21:07:40Z 2024-02-08T21:07:40Z 2021-04 Nature . 2021;592(7854):450-456. 10.1038/s41586-021-03362-0 1476-4687 Nature 33762733 http://hdl.handle.net/20.500.12105/17669 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. eng NASH limits anti-tumour surveillance in immunotherapy-treated HCC. journal article 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 URL https://repisalud.isciii.es/bitstreams/02274ab2-583b-473f-bb58-6a5bc4c0ec1c/download File MD5 8de690e286fc64ba658588c8c46e5fad 90519505 application/pdf NASHlimitsanti-tumour_2021.pdf URL https://repisalud.isciii.es/bitstreams/33aa8d14-1028-4199-b625-d1a17c912eaa/download File MD5 8de690e286fc64ba658588c8c46e5fad 90519505 application/pdf NASHlimitsanti-tumour_2021.pdf URL https://repisalud.isciii.es/bitstreams/c0b93a15-a5e6-4dcc-b18e-7d5d6e61b3ac/download File MD5 39ae7d5d4a643d15375bb2c18a912614 161663 text/plain NASHlimitsanti-tumour_2021.pdf.txt