Tumor evasion of the immune system by converting CD4+ CD25- T cells into CD4+ CD25+ T regulatory cells:: Role of tumor-derived TGF-β

CD4(+)CD25(+) T regulatory (T-reg) cells were initially described for their ability to suppress autoimmune diseases in animal models. An emerging interest is the potential role of T-reg cells in cancer development and progression because they have been shown to suppress antitumor immunity. In this study, CD4(+)CD25(-) T cells cultured in conditioned medium (CM) derived from tumor cells, RENCA or TRAMP-C2, possess similar characteristics as those of naturally occurring T-reg cells, including expression of Foxp3, a crucial transcription factor of T-reg cells, production of low levels of IL-2, high levels of IL-10 and TGF-beta, and the ability to suppress CD4(+)CD25(-) T cell proliferation. Further investigation revealed a critical role of tumor-derived TGF-beta in converting CD4(+)CD25(-) T cells into T-reg cells because a neutralizing Ab against TGF-beta, 1D11, completely abrogated the induction of T-reg cells. CM from a nontumorigenic cell line, NRP-152, or irradiated tumor cells did not convert CD4(+)CD25- T cells to T-reg cells because they produce low levels of TGF-beta in CM. Finally, we observed a reduced tumor burden in animals receiving 1D11. The reduction in tumor burden correlated with a decrease in tumor-derived TGF-beta. Treatment of 1D11 also reduced the conversion of CD4(+) T cells into T-reg cells and subsequent T-reg cell-mediated suppression of antitumor immunity. In summary, we have demonstrated that tumor cells directly convert CD4(+)CD25(-) T cells to T-reg cells through production of high levels of TGF-beta, suggesting a possible mechanism through which tumor cells evade the immune system.