NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Abstract

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.

Efficacy of Lenvatinib for Unresectable Hepatocellular Carcinoma Based on Background Liver Disease Etiology: Multi-center Retrospective Study

“…In a meta-analysis by P ster, patients with a viral etiology showed therapeutic bene ts with ICI treatment [HR 0.64], whereas those with nonviral etiology HCC did not [HR 0.92] (P=0.03) 5 . That study also presented results of two different validation studies of ICI treatment for HCC, in which NAFLD-HCC cases showed signi cantly worse OS than HCC with other etiology (HR 2.6 95%CI 1.2-5.6, P=0.017; median 8.8 vs. 17.7 months, P=0.034) 5 . In patients undergoing ICI treatment, background liver disease etiology might be a biomarker ofe cacy.…”

“…In spite of the good therapeutic response noted for Atezo+Bev in the IMbrave 150 trial, a recent report noted that therapeutic responses to ICI treatments differed according to the etiology of the background liver disease 5 . Meta-analysis of that report 5 indicated that patients with HCC with a viral etiology showed therapeutic bene ts from ICI use [HR 0.64], whereas those with a nonviral etiology did not [HR 0.92] (P=0.03).Most importantly, results of two validation cohorts treated with ICI clearly showed that overall survival (OS) for non-alcoholic fatty liver disease or non-alcoholic steatohepatitis (NAFLD/NASH)related HCC patients was signi cantly worse than that for the non-NAFLD/NASH-related HCC group (11.0 vs. 5.4 months, P=0.023 and 17.7 vs. 8,8 months, P=0.034, resspectively) 5 . This is the rst epoch-making and striking results that ICI treatment response differs based on background liver disease etiology, especially NASH/NAFLD related HCC lacks immune response and immune surveillance to the tumor associated antigen.…”

Mechanisms and disease consequences of nonalcoholic fatty liver disease

“…Although none has yet been compiled for NASH-HCC, similar efforts are underway and are likely to uncover novel, actionable targets for chemopreventive or treatment strategies in individuals at high risk or those with HCC. Recent mouse models and clinical data indicate that NASH-HCC 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, 2021).…”

Recent Advances and Future Prospects in Immune Checkpoint (ICI)-Based Combination Therapy for Advanced HCC

“…Last but not least, the efficacies of ICIs in HCCs of different etiologies should be clarified, in particular in non-alcoholic steatohepatitis (NASH) [115]. In a recent metaanalysis of the results of the CheckMate-459, IMbrave150, and Keynote-240 trials, non-viral (alcoholic or NASH) patients had no superior survival compared to the control arms, unlike HBV/HCV-related HCC patients [115]. Furthermore, non-alcoholic fatty liver disease (NAFLD) was independently associated with shortened median OS after immunotherapy.…”