Immune Regulation of Liver Cancer: Chronic Hepatitis Promotes HCC Development by Dismantling Cancer Immunosurveillance
Michael Karin and Shabnam Shalapour
University of California, San Diego, La Jolla, CA, USA
Chronic hepatitis caused by hypernutrition (NASH) or alcohol consumption (ASH) increases the risk of hepatocellular carcinoma (HCC), the major form of primary liver cancer and the second leading cause of cancer related death. By investigating clinical specimens a highly appropriate mouse model of NASH in which HCC development depends on ongoing oxidative stress we found that chronic liver inflammation and fibrosis results in accumulation of IgA+ immunosuppressive plasmocytes (ISP) that express the immunoregulatory molecules PD-L1 and IL-10. By engaging PD-1, ISP induce the exhaustion of liver infiltrating CD8+ T cells, some of which recognize tumor specific antigens that are expressed by HCC progenitor cells (HcPC). This allows the growth of HcPC into established HCC, a malignant progression that is even further accelerated by total CD8+ T cell ablation. Conversely, genetic and pharmacological interventions that reactivate exhausted CD8+ T cells and unleash their cytotoxic activity result in the regression of established HCC. These findings establish the importance of immunosurveillance in preventing liver cancer and the contribution of a specific immunosuppressive mechanism in alcohol and obesity induced HCC.