Regulatory T cells control anti-tumor microglia function in breast cancer brain metastasis

Breast cancer brain metastasis (BCBM) is linked with dismal outcomes. Current therapies fail due to their inability to cross the blood-brain barrier (BBB). Targeting immune cells in BCBM has garnered interest since immune cells naturally cross the BBB. Thus, there is a critical need to elucidate the immune microenvironment within BCBM. Regulatory T cells (Tregs) are immunosuppressive T cells implicated in several malignancies. However, their functions remain poorly understood in BCBM. Here we demonstrate that Tregs readily infiltrate the brain and suppress microglial responses to BCBM. Systemic Treg depletion in BCBM-bearing mice led to a massive accumulation of T cells and complete clearance of metastasis. We also found that microglia displayed a robust antigen presentation phenotype in Treg-depleted mice. Localized Treg depletion in the brain resulted in preferential expansion of conventional CD4 T cells (Tconv) 24h after Treg depletion and enrichment of antigen presentation in microglia at 48h. In situ analysis showed that Tregs and microglia co-localize at the tumor-stroma interface, indicating crosstalk between these two populations. Strikingly, microglia depletion reversed tumor clearance after Treg loss and significantly reduced Tconv infiltration. Preliminary analysis of available scRNAseq data of human brain metastases and mouse BCBM samples suggests that Treg-mediated suppression of microglia occurs through TIGIT-NECTIN2 signaling. Our data demonstrates that Tregs are central to BCBM progression through suppression of microglial antigen presentation and effector T cell responses. These findings identify Treg-mediated suppression of microglia as a central axis of immunosuppression in BCBM and a promising immunotherapeutic target.