HBV-specific CD4+ cytotoxic T cells in hepatocellular carcinoma are less cytolytic toward tumor cells and suppress CD8+ T cell-mediated antitumor immunity

In East Asia and sub-Saharan Africa, chronic infection is the main cause of the development of hepatocellular carcinoma, an aggressive cancer with low survival rate. Cytotoxic T cell-based immunotherapy is a promising treatment strategy. Here, we investigated the possibility of using HBV-specific CD4+ cytotoxic T cells to eliminate tumor cells. The naturally occurring HBV-specific cytotoxic CD4+ and CD8+ T cells were identified by HBV peptide pool stimulation. We found that in HBV-induced hepatocellular carcinoma patients, the HBV-specific cytotoxic CD4+ T cells and cytotoxic CD8+ T cells were present at similar numbers. But compared to the CD8+ cytotoxic T cells, the CD4+ cytotoxic T cells secreted less cytolytic factors granzyme A (GzmA) and granzyme B (GzmB), and were less effective at eliminating tumor cells. In addition, despite being able to secrete cytolytic factors, CD4+ T cells suppressed the cytotoxicity mediated by CD8+ T cells, even when CD4+ CD25+ regulator T cells were absent. Interestingly, we found that interleukin 10 (IL-10)-secreting Tr1 cells were enriched in the cytotoxic CD4+ T cells. Neutralization of IL-10 abrogated the suppression of CD8+ T cells by CD4+ CD25- T cells. Neither the frequency nor the absolute number of HBV-specific CD4+ cytotoxic T cells were correlated with the clinical outcome of advanced stage hepatocellular carcinoma patients. Together, this study demonstrated that in HBV-related hepatocellular carcinoma, CD4+ T cell-mediated cytotoxicity was present naturally in the host and had the potential to exert antitumor immunity, but its capacity was limited and was associated with immunoregulatory properties.