fig1

Figure 1. Cancer-immunity cycle and targets of immune therapies. Hepatocellular carcinoma (HCC) cells produce various tumor-associated antigens (TAAs) and neoantigens; the latter derive cancer-specific somatic mutations. The initial steps of anti-tumor immune response include uptake of TAAs and neoantigens by dendric cells (DCs). After that, the DCs migrate into regional lymph nodes and present processed antigen to CD4+ T cells. Antigen recognition leads to proliferation of CD4+ T cells and induction of interferon (IFN)-γ in the presence of IL-12 and type I IFN (Th1 polarization). The cross-presentation of antigenic peptide to CD8+ T cells by DCs facilitates the development of antigen-specific CD8+ cytotoxic T lymphocytes (CTLs). After the trafficking of CTLs to HCC tissues, the antigen-specific CTLs exert anti-tumor effecter function through release of humoral factors, such as granzyme B and perforin, and interaction with death receptors on tumor cells. Locoregional therapies and systemic chemotherapies should enhance the release of neoantigens and TAAs through HCC cell death. Cancer vaccines can promote the antigen presentation; anti-CTLA-4 antibody mainly acts in priming phase and facilitates the Th1 polarization and activation of CD8+ T cells. Adoptive immune therapies (immune cell transfer) increase the peripheral anti-tumor immune cells; chimeric antigen receptor (CAR) T cells can more directly targets cancer cells compared to conventional adoptive immunotherapies. Anti-vascular endothelial growth factor (VEGF) potentially induce infiltration of T cell into tumor tissues. Anti-PD-1/PD-L1 antibodies block the co-inhibitory signal of CD8+ T cells and induce cancer cell killing. CTLA-4: cytotoxic T lymphocyte associated antigen-4; PD-1: programmed cell death 1 protein; PD-L1: PD-1 ligand