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.

Background:There is increasing evidence that the presence of an ongoing systemic inflammatory response is a stage-independent predictor of poor outcome in patients with cancer. The aim of this study was to investigate whether an inflammation-based prognostic score, the prognostic nutritional index (PNI), is associated with overall survival (OS) in patients with hepatocellular carcinoma (HCC).Methods:All patients with a new diagnosis of HCC presenting to the Medical Oncology Department, Hammersmith Hospital between 1993 and 2011 (n=112) were included. Demographic and clinical data were collected. Patients in whom the combined albumin (g l−1) × total lymphocyte count × 109 l−1 was ⩾45, at presentation, were allocated a PNI score of 0. Patients in whom this total score was <45 were allocated a score of 1. Univariate and multivariate analyses were performed to identify clinicopathological variables associated with OS. Independent predictors of survival identified on multivariate analysis were validated in an independent, stage-matched cohort of 68 patients.Results:Univariate analyses showed that PNI (P=0.003), intrahepatic spread (P<0.001), the presence of extrahepatic disease (P=0.006), portal vein thrombosis (P=0.02), tumour multifocality (P=0.003), alfa-fetoprotein >400 ng ml−1 (P<0.001) and Barcelona Clinic Liver Cancer score (P<0.01) were all predictors of OS in the training set. Multivariate analysis revealed the PNI (P=0.05), presence of extrahepatic disease (P<0.001) and degree of intrahepatic spread (P<0.001) as independent predictors of worse OS in this population. The PNI retained independent prognostic value in the validation set (P<0.001).Conclusion:The presence of a systemic inflammatory response, as measured by the PNI, is an independent and externally validated predictor of poor OS in patients with HCC.