Emergence of immunotherapy as a novel way to treat hepatocellular carcinoma

Abstract

Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen presenting cells (APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor immunity is frequently repressed at tumor sites. Malignantly transformed cells rarely survive the attack by the immune system, but cells that do survive change their phenotypes to reduce their immunogenicity. The resultant cells evade the attack by the immune system and form clinically discernible tumors. Tumor microenvironments simultaneously contain a wide variety of immune suppressive molecules and cells to dampen tumor immunity. Moreover, the liver microenvironment exhibits immune tolerance to reduce aberrant immune responses to massively-exposed antigens via the portal vein, and immune dysfunction is frequently associated with liver cirrhosis, which is widespread in hepatocellular carcinoma (HCC) patients. Immune therapy aims to reduce tumor burden, but it is also expected to prevent non-cancerous liver lesions from progressing to HCC, because HCC develops or recurs from non-cancerous liver lesions with chronic inflammatory states and/or cirrhosis and these lesions cannot be cured and/or eradicated by local and/or systemic therapies. Nevertheless, cancer immune therapy should augment specific tumor immunity by using two distinct measures: enhancing the effector cell functions such as antigen presentation capacity of APCs and tumor cell killing capacity of cytotoxic cells, and reactivating the immune system in immune-suppressive tumor microenvironments. Here, we will summarize the current status and discuss the future perspective on immune therapy for HCC.

Keywords: Natural killer T cell, Natural killer cell, Chimeric antigen receptor T cell, T cell receptor, Cytokine-induced killer cell, Program death-1, Cytotoxic lymphocyte antigen-4, Regulatory T cell, Dendritic cell, Myeloid-derived suppressor cell, PD-ligand 1, Peptide vaccine, Tumor-associated antigen, Tumor infiltrating lymphocyte

Core tip: Hepatocellular carcinoma (HCC) develops or recurs from non-cancerous liver lesions with chronic inflammatory states and/or cirrhosis, and these lesions cannot be cured and/or eradicated by local and/or drug therapies. Immune therapy may be effective for HCC treatment by preventing non-cancerous liver lesions from progressing to HCC as well as reducing tumor burdens. However, tumor immunity is frequently depressed in tumor sites, particularly in liver microenvironment, which is prone to exhibit immune tolerance, to reduce aberrant immune responses to massively-exposed antigens via portal veins. At present, cancer immune therapy employs two distinct strategies; enhancing the effector cell functions and unleashing the immune suppressive tumor microenvironments. Here, we will summarize the current status and discuss the future perspective on immune therapy for HCC.