期刊
NATURE
卷 592, 期 7854, 页码 450-456出版社
NATURE PORTFOLIO
DOI: 10.1038/s41586-021-03362-0
关键词
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资金
- 'Deutsche Forschungsgemeinschaft' (DFG, Bonn Germany) through Emmy Noether program [SI 2620/1-1]
- EMBO LT fellowship [ALTF 539-2018]
- EPoS (Elucidating Pathways of Steatohepatitis) consortium - Horizon 2020 Framework Program of the European Union [634413]
- LITMUS (Liver Investigation: Testing Marker Utility in Steatohepatitis) consortium - Innovative Medicines Initiative (IMI2) Program of the European Union [777377]
- Newcastle NIHR Biomedical Research Centre
- Chan Zuckerberg Initiative (CZI)
- HHMI international scholar award
- European Research Council consolidator grant (ERC-COG) [724471-HemTree2.0]
- Thompson Family Foundation
- MRA established investigator award [509044]
- Israel Science Foundation [703/15]
- Ernest and Bonnie Beutler Research Program for Excellence in Genomic Medicine
- Helen and Martin Kimmel award for innovative investigation
- NeuroMac DFG/Transregional Collaborative Research Center grant
- Adelis Foundation
- SCA award of the Wolfson Foundation
- Cancer Research UK [C9380/A26813, C57701/A26137]
- Fondazione AIRC [C9380/A26813]
- Fundacion Cientifica de la Asociacion Espanola Contra el Cancer (HUNTER) [C9380/A26813]
- European Commission (EC)/Horizon 2020 Program (HEPCAR) [667273-2]
- US Department of Defense [CA150272P3]
- NCI Cancer Center Support Grant
- Tisch Cancer Institute [P30-CA196521]
- Samuel Waxman Cancer Research Foundation
- Spanish National Health Institute [SAF2016-76390, PID2019-105378RB-I00]
- Generalitat de Catalunya/AGAUR [SGR-1358]
- HEPCAR
- Rio Hortega grant from the ISCIII [CM19/00039]
- European Social Fund
- AECC
- Swiss National Science Foundation (SNF)
- ERC Consolidator grant (HepatoMetaboPath)
- Wilhelm Sander-Stiftung
- Research Foundation Flanders (FWO) [30826052]
- Deutsche Krebshilfe projects [70113166, 70113167]
- German-Israeli Cooperation in Cancer Research (DKFZ-MOST)
- Helmholtz-Gemeinschaft, Zukunftsthema 'Immunology and Inflammation' [ZT-0027]
- German Research Foundation [HA 8754/1-1]
- 'Deutsche Forschungsgemeinschaft' (DFG) [259332240/RTG 2099]
- Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ)
- Israel's Ministry of Science, Technology and Space (MOST) [CA181]
- Wellcome Trust Strategic Fund [PS3416]
- ASCO/Conquer Cancer Foundation Global Oncology Young Investigator Award 2019 [14704]
- Westminster Medical School Research Trust [JRC SG 009 2018-19]
- German Cancer Aid [70113167, 70112720]
- Swiss National Foundation
- Swiss Foundation against Liver Cancer
- DFG [Me3644/5-1]
- Elke-Kroner-Fresenius foundation
- Deutsche Forschungsgemeinschaft [FOR2314, SFB-TR209]
- German Ministry for Education and Research (BMBF)
- DFG under Germany's excellence strategy [EXC 2180-390900677]
- Landesstiftung Baden-Wuerttemberg
- European Research Council (CholangioConcept)
- German Cancer Research Center (DKTK)
- Swiss National Science Foundation [733 310030_170320, 316030_150768, CRSII5_183478]
- Swiss Cancer League
- University Research Priority Program (URPP) postdoctoral fellowship
- SNF Project Grant [310030 182679]
- Canica Holding Research Grant
- Norwegian PSC Research Center
- Stiftung zur Krebsbekampfung
- Bangerter-Rhyner Stiftung
- Dangel Stiftung
- Helmholtz Future topic Inflammation and Immunology
- BMBF [031B0686B]
- International Progressive MS Alliance/NMSS [PA-1604-08459]
- National Cancer Institute
- Rainer Hoenig Stiftung
- Horizon 2020 grant (Hepcar)
- CW+
- [SFB 1335]
- [SFBTR179]
- [272983813]
- [SFB/TR 209]
- [314905040]
- [SFBTR1335]
- [360372040]
- Swiss National Science Foundation (SNF) [310030_182679] Funding Source: Swiss National Science Foundation (SNF)
The study investigated the impact of NASH on immunotherapy response in HCC patients and found that NASH-HCC may be less responsive to immunotherapy. Aberrant T cell activation caused by NASH-related tissue damage led to impaired immune surveillance in HCC patients.
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.
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