Immune checkpoint blockade in hepatocellular carcinoma: current progress and future directions

Abstract

Immune checkpoint blockade has recently emerged as a promising therapeutic approach for various malignancies including hepatocellular carcinoma (HCC). Preclinical and clinical studies have shown the potential benefit of modulating the immunogenicity of HCC. In addition, recent advances in tumor immunology have broadened our understanding of the complex mechanism of immune evasion. In this review we summarize the current knowledge on HCC immunology and discuss the potential of immune checkpoint blockade as a novel HCC therapy from the basic, translational, and clinical perspectives.

Figure 1. Role of immune checkpoint molecules in anti-tumor immune responses against hepatocellular carcinoma

(a) Cancer cells enhance the intratumoral recruitment and expansion of MDSCs and Tregs. Tregs and MDSCs suppress innate immune response of NK cells through activation of immune checkpoint pathways such as PD-L1/PD-1. MDSC or Treg activity is regulated by the inflammatory tumor microenvironment, helper T cells or dendritic cell activities. (b) The acquired immune responses are suppressed through multiple mechanisms by immune checkpoint molecules. Cytotoxic T cell function is not only subdued by the immune suppressive cells such as Tregs and MDSCs but also repressed by the co-stimulation of CTLA-4 with antigen presentation from DCs. The tolerogenic liver microenvironment also inhibits cytotoxic T cell activation.