CXCR3+ T Regulatory Cells Selectively Accumulate in Human Ovarian Carcinomas to Limit Type I Immunity

Antitumor type I T-cell responses involving IFN-gamma production are critical to control cancer, but the efficacy of this response is limited by a variety of immunosuppressive mechanisms that promote tumoral immune escape. One critical mechanism involves the accumulation of FOXP3(+) T regulatory cells (Treg), a class of suppressive T cells that prevent excessive tissue destruction caused by unchecked immune responses. Recent studies have revealed that FOXP3(+) Treg include distinct subsets specifically controlling over the corresponding effector subset. In particular, CXCR3(+) Treg have been described as a subset specialized in the control of type I T-cell responses in vivo. Here, we show that CXCR3(+) Treg are highly enriched in human ovarian carcinomas, particularly in solid tumor masses, where they represent the majority of Treg. Tumor-associated CXCR3(+). Treg coexpress T-bet but do not secrete IFN-g ex vivo and suppress proliferation and IFN-gamma secretion of T effectors. In addition, they coexpress Helios, suggesting that they originate from natural Treg. Finally, we show that the proportion of CXCR3(+) Treg at tumor sites is directly correlated with that of CXCR3(+) T effectors, consistent with expression of CXCR3 ligands. Together, our findings support the concept that natural CXCR3(+) T-bet(+) Treg selectively accumulate in ovarian tumors to control type I T-cell responses, resulting in the collateral limitation of efficient antitumor immunity. Cancer Res; 72(17); 4351-60. (c) 2012 AACR.