“…Thus, NASH precluded efficient anti-tumour surveillance in the context of HCC immunotherapy. Similarly, impaired immunotherapy has been described in mouse models with NASH and secondary liver cancer 25 , 26 .…”
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.
“…Thus, NASH precluded efficient anti-tumour surveillance in the context of HCC immunotherapy. Similarly, impaired immunotherapy has been described in mouse models with NASH and secondary liver cancer 25 , 26 .…”
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.
“…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).…”
“…Emerging data suggest that changes in the local immune microenvironment and gut dysbiosis may hamper the efficacy of immunotherapy in NASH-HCC. 79 , 82 , 84 These data are preliminary and need validation in prospective studies. Hence, based on the current evidence, immunotherapy should not be withheld from patients with NASH-HCC.…”
Section: Resultsmentioning
confidence: 95%
“…Prevention of intratumoral T-cell loss recovered efficacy of immunotherapy. 82 Figure 2 Factors promoting immunosuppression in patients with non-alcoholic fatty liver disease. NAFLD impacts the liver immune microenvironment.…”
Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent and increasing liver disease, which encompasses a variety of liver diseases of different severity. NAFLD can lead to liver cirrhosis with all its complications as well as hepatocellular carcinoma (HCC). Steatosis of the liver is not only related to obesity and other metabolic risk factors, but can also be caused by several drugs, including certain cytotoxic chemotherapeutic agents. In patients undergoing liver surgery, hepatic steatosis is associated with an increased risk of post-operative morbidity and mortality. This review paper summarizes implications of hepatic steatosis on the management of patients with cancer. Specifically, we discuss the epidemiological trends, pathophysiological mechanisms, and management of NAFLD, and its role as a leading cause of liver cancer. We elaborate on factors promoting immunosuppression in patients with NAFLD-related HCC and how this may affect the efficacy of immunotherapy. We also summarize the mechanisms and clinical course of chemotherapy-induced acute steatohepatitis (CASH) and its implications on cancer treatment, especially in patients undergoing liver resection.
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