Regulatory T Cells Support Breast Cancer Progression by Opposing IFN-γ-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-γ-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-γ signaling pathway in monocytes. [Display omitted] •Anti-tumor phenotype requires reprogramming of inflammatory monocytes/macrophages•Myeloid cell functional reprogramming is dependent on IFN-γ produced by CD4T cells•TAM reprogrammed transcriptome correlates with better prognosis in human cancer Treg cells correlate with poor prognosis in breast cancer, yet we lack mechanistic insights on how they promote tumorigenesis. Clark et al. demonstrate that anti-tumor effects following Treg cell ablation in murine breast tumors require IFN-γ-dependent functional reprogramming of inflammatory monocytes/TAMs and correlate with prognosis in human breast cancer.