Immunology of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is primarily a malignancy of the liver, advancing from a damaged, cirrhotic liver to HCC. Globally, HCC is the sixth most prevalent cancer and the third-most prevalent reason for neoplastic disease-related deaths. A diverse array of infiltrating immunocytes regulates the development and progression of HCC, as is the case in many other cancers. An understanding of the various immune components during HCC becomes necessary so that novel therapeutic strategies can be designed to combat the disease. A dysregulated immune system (including changes in the number and/or function of immune cells, cytokine levels, and the expression of inhibitory receptors or their ligands) plays a key role in the development of HCC. Alterations in either the innate or adaptive arm of the immune system and cross-talk between them make the immune system tolerant to tumors, leading to disease progression. In this review, we have discussed the status and roles of various immune effector cells (e.g., dendritic cells, natural killer cells, macrophages, and T cells), their cytokine profile, and the chemokine-receptor axis in promoting or impeding HCC.

Keywords: Adaptive immunity; Hepatocellular carcinoma; Immune cells; Immune-dysregulation; Innate immunity.

Figure 1

Role of immune cells in hepatocellular carcinoma. As the disease progresses from cirrhosis of the liver to hepatocellular carcinoma (HCC), the functions of various immune cells become dysregulated. Dendritic cells (DCs) lose their antigen presentation capabilities with the reduced secretion of Th1 cytokines. Macrophages differentiate into an “alternatively-activated phenotype” that generates a Th2-type immune response that promotes regulatory T cell (Tregs) recruitment and development. Natural killer (NK) cells have reduced cytolytic activities. T cells, both CD4⁺ and CD8⁺, decrease in numbers with attenuated function and increased expression of inhibitory receptors during HCC. Th17 cells increase in number and correlate with angiogenesis and poor-prognosis. Tregs exert negative effects on T cells, DCs, and NK cells, and may promote the differentiation of Th17 cells via immunosuppressive cytokines. There is shift in overall cytokine milieu from a Th1 to Th2 profile. HBV: Hepatitis B virus; HCV: Hepatitis C virus; IL-12: Interleukin 12; TGF: Transforming growth factor.