Impaired Th1 immunity in ovarian cancer patients is mediated by TNFR2Â + Tregs within the tumor microenvironment

•TNFR2 + Tregs are present at high levels within the ascites of ovarian cancer.•Ascitic TNFR2 + Tregs are more suppressive compared to peripheral blood TNFR2 + Tregs.•Ascitic TNFR2 + Tregs express high levels of multiple suppressive mediators.•TNFR2 + Tregs are more capable of migrating into tumor ascites.•TNFR2 + Tregs can dampen local IFNγ and IL2 production by effector T cells.

Ovarian cancer is a prevalent gynecological malignancy with potent immune-suppression capabilities; regulatory T cells (Tregs) are significant contributors to this immune-suppression. As ovarian cancer patients present with high levels of TNF and Tregs expressing TNFR2 are associated with maximal suppressive capacity, we investigated TNFR2 + Tregs within these patients. Indeed, TNFR2 + Tregs from tumor-associated ascites were the most potent suppressor T cell fraction. They were abundantly present within the ascites and more suppressive than peripheral blood TNFR2 + Tregs in patients. The increased suppressive capacity can be explained by a distinct cell surface expression profile, which includes high levels of CD39, CD73, TGF-β and GARP. Additionally, CD73 expression level on TNFR2 + Tregs was inversely correlated with IFN-γ production by effector T cells. This Treg fraction can be selectively recruited into the ascites from the peripheral blood of patients. Targeting TNFR2 + Tregs may offer new approaches to enhance the poor survival rates of ovarian cancer.