Regulatory T cells support breast cancer progression by opposing IFN-? -dependent functional reprogramming of myeloid cells

Regulatory T (Treg) cell infiltration of solid tumors often correlates with poor prognosis, but their tumor suppressive function lacks mechanistic understanding. Through a combination of transgenic mice, cell fate mapping, adoptive transfer and co-injection strategies, we demonstrate that Treg cell ablation-dependent anti-tumor effects in murine breast cancer require intratumoral recruitment of CCR2+ inflammatory monocytes, which primarily differentiate into tumor-associated macrophages (TAMs), and lead to reprogramming of their function in an IFN-?-dependent manner. Furthermore, transcriptomic signatures from murine TAMs in Treg cell-ablated conditions correlate with increased overall survival in human breast cancer. Our studies highlight the strong myeloid dependency of breast cancer, and provide the basis for the development of therapeutic strategies based on manipulation of the IFN-? signaling pathway in monocytes. Overall design: We mechanistically dissect the tumor-promoting function of Treg cells in poorly immunogenic breast cancer, describing the critical role of TAMs in the anti-tumor phenotype observed upon Treg cell ablation, and the dependency on CD4+ T cell-produced IFN-? for their functional reprogramming