Hepatitis B virus (HBV)-related hepatocellular carcinoma is a common, but aggressive liver cancer with a low survival rate. Given the immunogenicity of HBV and tumor cells, immunotherapies based on T-cell cytotoxicity may be viable treatment approaches to hepatocellular carcinoma. Studies were conducted to characterize the cytotoxic T-cell (CD4+ and CD8+) responses involved in HBV-related hepatocellular carcinoma.
Tumor samples and peripheral blood mononuclear cells (PBMCs) were collected from patients with HBV-related hepatocellular carcinoma and cultured. Naturally occurring HBV-speciﬁc CD4+ and CD8+ cytotoxic T cells were identified in PBMCs using HBV peptide pool stimulation. This method involves stimulating T cells by incubating PMBCs with a combination of synthetic peptides (antigens) covering specific HBV genotypes. The identified CD4+ and CD8+ cytotoxic T cells were added to cultured chromium-labeled tumor cells. Tumor cell lysis was determined by measuring chromium release, and the amount of GzmA, GzmB, and perforin (cytolytic molecules) secretion by CD4+ and CD8+ cytotoxic T cells were examined using ELISA kits.
Although no differences in degranulation capacity were observed between CD4+ and CD8+ cytotoxic T cells, CD4+ cells secreted less GzmA and GzmB (no significant changes in perforin levels observed), than a comparable number of CD8+ cytotoxic T cells. The CD4+ cytotoxic T cells induced a lower level of tumor cell lysis than the CD8+ cells. When examining the effects of adding CD4+ and CD8+ cells together in culture, the CD4+ cells were found to cause a reduction in CD8+ cytotoxic T cell-induced tumor cell lysis. Examination of the role of CD4+ T cell−expressed IL-10 in the reduction of CD8+ T cell cytotoxicity was achieved by coculturing both T-cell types with tumor cells with or without anti-IL-10 antibodies. Neutralization of IL-10 restored CD8+ cytotoxic T cell toxicity despite the presence of CD4+ T cells.
Overall, CD4+ cytotoxic T cells are less cytotoxic to tumor cells and secrete less cytolytic factors than CD8+ T cells. In addition to being less cytotoxic, CD4+ T cells suppress CD8+ T cell cytotoxicity, which is associated with the secretion of IL-10. Therefore, CD4+ cytotoxic T cells can work for and against the fight against hepatocellular carcinoma.
Meng, F., Zhen, S., & Song, B. (2017). HBV-specific CD4+ cytotoxic T cells in hepatocellular carcinoma are less cytolytic toward tumor cells and suppress CD8+ T cell-mediated antitumor immunity. APMIS. doi:10.1111/apm.12704