Data from CXCR3<sup>+</sup> T Regulatory Cells Selectively Accumulate in Human Ovarian Carcinomas to Limit Type I Immunity

Antitumor type I T-cell responses involving IFN-γ 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-γ ex vivo and suppress proliferation and IFN-γ 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. ©2012 AACR.