Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival

Abstract

Regulatory T (T_reg) cells mediate homeostatic peripheral tolerance by suppressing autoreactive T cells. Failure of host antitumor immunity may be caused by exaggerated suppression of tumor-associated antigen–reactive lymphocytes mediated by T_reg cells; however, definitive evidence that T_reg cells have an immunopathological role in human cancer is lacking. Here we show, in detailed studies of CD4⁺CD25⁺FOXP3⁺ T_reg cells in 104 individuals affected with ovarian carcinoma, that human tumor T_reg cells suppress tumor-specific T cell immunity and contribute to growth of human tumors in vivo. We also show that tumor T_reg cells are associated with a high death hazard and reduced survival. Human T_reg cells preferentially move to and accumulate in tumors and ascites, but rarely enter draining lymph nodes in later cancer stages. Tumor cells and microenvironmental macrophages produce the chemokine CCL22, which mediates trafficking of T_reg cells to the tumor. This specific recruitment of T_reg cells represents a mechanism by which tumors may foster immune privilege. Thus, blocking T_reg cell migration or function may help to defeat human cancer.