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.