Connecting blood and intratumoral Treg 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(H)1) and T helper type 2 (T(H)2) 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.