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Tumor Evasion of the Immune System by Converting CD4⁺CD25^– T Cells into CD4⁺CD25⁺ T Regulatory Cells: Role of Tumor-Derived TGF-

Victoria C. Liu^*, Larry Y. Wong^*, Thomas Jang^*, Ali H. Shah^*, Irwin Park^*, Ximing Yang^*, Qiang Zhang^*, Scott Lonning, Beverly A. Teicher and Chung Lee^1,*

^* Department of Urology, Northwestern University Medical School, Chicago, IL 60611; and Genzyme, Framingham, MA 01701

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-, and the ability to suppress CD4⁺CD25^– T cell proliferation. Further investigation revealed a critical role of tumor-derived TGF- in converting CD4⁺CD25^– T cells into T_reg cells because a neutralizing Ab against TGF-, 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- 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-. 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-, suggesting a possible mechanism through which tumor cells evade the immune system.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Chung Lee, Department of Urology, Tarry 16-733, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611. E-mail address: c-lee7{at}northwestern.edu

² Abbreviations used in this paper: TIL, tumor-infiltrating lymphocyte; CM, conditioned medium; DC, dendritic cell; T_reg, T regulatory.

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