The immunosuppressive tumor microenvironment in hepatocellular carcinoma and the identification of a new type of Foxp3‐expressing cell

Abstract

Increasing evidence supports the existence of many immunosuppressive factors in tumor microenvironment. To investigate the immune status in hepatocellular carcinoma tissues, we isolated tumor infiltrating lymphocytes (TILs) and non‐tumor infiltrating lymphocytes (NILs) from fresh tissue. In comparison to NILs, CD4+ T cells in TILs were elevated, whereas CD8+ T cells, NK cells, CD56+ T cells, γδT cells, and CCR7−CD45RA+CD8+ cells were reduced. Moreover, CD8+ cells in TILs showed impaired capacity for the production of IFN‐γ and perforin. Reduced IFN‐γ production was also observed for CD4+ cells. On the other hand, these cells secreted more IL‐10. Subsequently, we examined the representation of cells with suppressive functions. TILs were found to contain a markedly increased number of CD4+CD25+Foxp3+, CD3+CD56+Foxp3+, and CD3−CD56+Foxp3+ cells. Further analysis of the CD3+CD56+Foxp3+ cells demonstrated that they were mainly CD8−CD4+Valpha24− cells, which produced significant amount of IL‐4 and IL‐10, but rarely IFN‐γ or perforin. In conclusion, the hepatocellular carcinoma microenvironment appears to be dominated by negative immune regulators, and the CD3+CD56+Foxp3+ cells may represent a new type of regulatory cells.