Preferential accumulation of regulatory T cells with highly immunosuppressive characteristics in breast tumor microenvironment

Abstract

Immunosuppressive cells such as regulatory T cells (Tregs) have an ambiguous role in breast cancer prognosis, with studies reporting both positive and negative correlations between Treg infiltration and prognosis. This discrepancy could be due to the different immunosuppressive molecules present in these cells. In the present study, we phenotypically characterize different Treg subsets infiltrating the tumor microenvironment (TME), compared to adjacent normal tissue and peripheral blood of primary breast cancer (PBC) patients. We report that the majority of tumor-infiltrating CD4⁺ and CD8⁺ T cells have terminally exhaustive phenotype as assessed by CD39 and PD-1 expressions. We also show that Tregs are accumulated in breast TME compared to normal tissue. Further characterization of Tregs showed that these are mainly FoxP3⁺Helios⁺ and express high levels of CTLA-4 and PD-1. This preferential accumulation of FoxP3⁺Helios⁺ Treg subset with co-expression of different immune inhibitory molecules might have a negative effect on breast cancer prognosis. Taken together, our results suggest that breast tumor cells might utilize Tregs, and different suppressive pathways involving CD39, PD-1 and CTLA-4 molecules in creating an immune-subversive environment for them to survive, and a dual blockade of these immunosuppressive molecules might be considered as an effective method in breast cancer treatment.