NASH limits anti-tumour surveillance in immunotherapy-treated HCC

By D. Pfister, N. Núñez, R. Pinyol, O. Govaere, M. Pinter, M. Szydlowska, Revant Gupta, Mengjie Qiu, A. Deczkowska, A. Weiner and 100 more. Nature, 2021

1,066 citations recorded by the source corpus.

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. In hepatocellular carcinoma driven by non-alcoholic steatohepatitis, aberrant T cell activation and impaired immune surveillance seem to make hepatocellular carcinoma less responsive to anti-PD1 or anti-PDL1 immunotherapy.

Subfields: Epidemiology, Immunology

View Paper: https://www.semanticscholar.org/paper/c0cd432dd00a5a0392dfe007be9480d2e1e6b3a9

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Citations in the corpus

MASLD: a systemic metabolic disorder with cardiovascular and malignant complications (2024, background): “90 91 Such a micromilieu might favour liver carcinogenesis, explaining why HCC evolves even in a non-cirrhotic liver.”
Global trends in hepatocellular carcinoma epidemiology: implications for screening, prevention and therapy (2023, background): “Differences in outcome with ICI-based regimens according to aetiology (in particular, lower efficacy against MASLD-related HCC versus HCCs of other aetiologies) remain controversial, with some studies suggesting differential activity and others not 223,240–242 .”
Hepatic inflammatory responses in liver fibrosis (2023, positive): “Importantly, CXCR6 is not specific to NKT cells but is present in several lymphocyte populations, including liver-resident CD8 + T cells in NASH that trigger auto-aggression against hepatocytes 58 and show dysfunctional tumour surveillance in mouse models of NASH 59 .”
Mechanisms and disease consequences of nonalcoholic fatty liver disease (2021, background): “Recent mouse models and clinical data indicate that NASHHCC is less responsive to emerging immunotherapies because of reduced infiltration of CD4 T cells, impaired immune surveillance, and NASH-related aberrant T cell activation, which induces tissue damage (Heinrich et al., 2021; Pfister et al., 20”