Connecting blood and intratumoral T_reg cell activity in predicting future relapse in breast cancer

Regulatory T (T_reg) cells play a major role in the development of an immunosuppressive tumor microenvironment. The origin of intratumoral T_reg cells and their relationship with peripheral blood T_reg cells remain unclear. T_reg cells consist of at least three functionally distinct subpopulations. Here we show that peripheral blood CD45RA^-FOXP3^hi T_reg cells (T_reg II cells) are phenotypically closest to intratumoral T_reg cells, including in their expression of CCR8. Analyses of T cell antigen receptor repertoires further support the hypothesis that intratumoral T_reg cells may originate primarily from peripheral blood T_reg II cells. Moreover, the signaling responsiveness of peripheral blood T_reg II cells to immunosuppressive, T helper type 1 (T_H1) and T helper type 2 (T_H2) cytokines reflects intratumoral immunosuppressive potential, and predicts future relapse in two independent cohorts of patients with breast cancer. Together, our findings give important insights into the relationship between peripheral blood T_reg cells and intratumoral T_reg cells, and highlight cytokine signaling responsiveness as a key determinant of intratumoral immunosuppressive potential and clinical outcome.