Composition and plasticity of triple-negative breast carcinoma-infiltrating regulatory T cells.

Low Foxp3 regulatory T-cell (Treg) presence in the tumor-infiltrating lymphocytes (TILs) is considered favorable in breast cancer, and numerous CD25-targeting agents have been applied in the attempt to remove Foxp3 Treg cells, which typically present CD4 CD25 surface phenotype. However, CD25 is not Treg-exclusive and can be upregulated by effector T cells. Hence, CD25 depletion may cause the elimination of activated T cells that are responding to tumor-specific antigens. In this study, the composition and function of CD4 CD25 cells inside the microenvironment of triple-negative breast carcinoma (TNBC) were investigated. Directly ex vivo, the Foxp3 Treg cells represented a minor subset in total CD4 CD25 TILs. Significant differences were observed in the expression of Treg-associated molecules between CD4 CD25 Foxp3 TILs and CD4 CD25 Foxp3 TILs. While both the CD4 CD25 Foxp3 and the CD4 CD25 Foxp3 TILs could express CTLA-4 and LAG-3, the expression levels were significantly higher in CD4 CD25 Foxp3 TILs than in CD4 CD25 Foxp3 TILs. Upon TCR stimulation, the expression of TGF-beta was significantly higher in CD4 CD25 Foxp3 TILs, while the expression of IL-10 was significantly higher in CD4 CD25 Foxp3 TILs. These differences were conserved in the blood counterparts of these cells. Interestingly, the level of CD25 Foxp3 cells in circulating CD4 T cells was positively correlated with the level of CD25 Foxp3 cells in CD4 TILs, but the level of CD25 Foxp3 cells in circulating CD4 T cells was not associated with the level of CD25 Foxp3 cells in CD4 TILs. Th17-polarizing medium could readily remodel CD4 CD25 Foxp3 , but not CD4 CD25 Foxp3 , T cells into RORgammat and IL-17-expressing T cells, demonstrating stronger plasticity of the former subset. Together, these data demonstrated that the CD4 CD25 TILs were composed of distinctive Foxp3 and Foxp3 cells, with the former representing the major subset. The antigen specificity and effector molecule expression of the CD4 CD25 Foxp3 thus require further analyses.