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.

Activating the immune system for therapeutic benefit in cancer has long been a dream of some immunologists, and even a few oncologists. After decades of disappointment, the tide has finally changed due to the success of recent proof-of-concept clinical trials. Most notable has been the ability of the anti-CTLA4 antibody ipilimumab to achieve significant increases in survival of patients with metastatic melanoma, an indication where conventional therapies have failed. Viewed in the context of advances in understanding of how tolerance, immunity, and immunosuppression regulate anti-tumor immune responses together with the advent of targeted therapies, these successes suggest that active immunotherapy represents a path forward to obtaining durable, long-lasting responses in cancer patients.

The presence of intratumoral T cells correlates with improved clinical outcome in advanced ovarian carcinoma.