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

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  • معلومة اضافية
    • Contributors:
      Deutsche Forschungsgemeinschaft (Alemania); European Molecular Biology Organization; Unión Europea. Comisión Europea. H2020; Howard Hughes Medical Institute; Israel Science Foundation; Cancer Research UK (Reino Unido); Asociación Española Contra el Cáncer; United States Department of Health and Human Services; Government of Catalonia (España); Instituto de Salud Carlos III
    • بيانات النشر:
      Nature Publishing Group
    • الموضوع:
      2021
    • Collection:
      REPISALUD (REPositorio Institucional en SALUD del Instituto de Salud Carlos III - ISCIII)
    • نبذة مختصرة :
      and ; 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 ...
    • ISSN:
      1476-4687
    • Relation:
      https://doi.org/10.1038/s41586-021-03362-0.; info:eu-repo/grantAgreement/ES/SAF2016-76390; info:eu-repo/grantAgreement/ES/PID2019-105378RB-I00; Nature . 2021;592(7854):450-456.; http://hdl.handle.net/20.500.12105/17669; Nature
    • الرقم المعرف:
      10.1038/s41586-021-03362-0
    • Rights:
      http://creativecommons.org/licenses/by-nc-nd/4.0/ ; Attribution-NonCommercial-NoDerivatives 4.0 Internacional ; open access
    • الرقم المعرف:
      edsbas.B3FB94C0