New insights into the pathogenesis and treatment of non-viral hepatocellular carcinoma: a balancing act between immunosuppression and immunosurveillance

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. HCC initiates as a consequence of chronic liver damage and inflammation caused by hepatitis B and C virus infections, excessive alcohol consumption, or non-alcoholic fatty liver disease (NAFLD). Until recently, no effective treatments for advanced HCC were available and the 5-year survival rate had remained below 8% for many years. New insights into the mechanisms that drive the development of NAFLD-related HCC indicate that loss of T-cell-mediated immunosurveillance plays a cardinal role in tumor growth and malignant progression, in addition to previously identified inflammation-driven compensatory proliferation. Recently completed groundbreaking clinical studies have shown that treatments that restore antitumor immunity represent a highly effective therapeutic option for approximately 20% of advanced HCC patients. Understanding the causes of inflammation-driven immunosuppression and immune system dysfunction in the 80% of patients who fail to reignite antitumor immunity despite treatment with checkpoint inhibitors should lead to further and even more dramatic improvements in HCC immunotherapy.

Figure 1.

Key molecular elements that dictate the balance between tumor immunity and inflammation-driven immunosuppression. Tfh, follicular helper T cells; ISP, immunosuppressive plasmocytes.