Regulatory T cells as key modulators of breast cancer brain metastasis

Abstract

Abstract Breast cancer brain metastasis (BCBM) is a disease with a dismal prognosis. Current therapeutics often fail due to the distinct immune environment within the brain. Thus, there is a critical need to understand infiltrating immune cells within BCBM. Regulatory T cells (Tregs) are a population of immunosuppressive T cells that have been implicated in the pathogenesis of several tumor types. Their functions are widely explored in these contexts, but an understanding of these functions in the brain is lacking. To elucidate the role of Tregs in BCBM, we intracranially injected E0771 cells into C57BL/6J mice and monitored tumor development and immune infiltration for 14 days. Using Foxp3-DTR mice, we assessed the effects of Treg depletion on tumor burden and the immune microenvironment. We found that Tregs prominently infiltrated BCBM tumors throughout tumor progression. Furthermore, Treg depletion led to a massive accumulation of CD8+ and CD4+ T cells and a near-complete loss of tumor burden. Additionally, we demonstrated that microglia, a population of brain-resident macrophages, displayed a more prominent antigen presentation phenotype in Treg-depleted mice. We hypothesize that BCBM-infiltrating Tregs suppress the infiltration and activation of CD8+ and CD4+ T cells by inhibiting antigen presentation in microglia. The mechanisms by which Tregs exert this function are unclear but can lead to the identification of novel therapeutic targets for the treatment of brain metastases.