Title: Microglial response to breast cancer brain metastasis at single-cell resolution
Abstract: Breast cancer brain metastasis (BCBM) affects 10-20% of breast cancer patients with a median survival time of less than two years and very few treatment options. An emerging possibility for these patients is drugs that alter the microenvironment of brain metastases to facilitate an anti-tumoral immune response. While promising, this treatment approach requires careful characterization of cell phenotypes present in the tumor niche as well as an understanding of how these cells can influence one another. To address this, we performed a cardiac injection of human breast cancer cells (MDA-MB-231) in Foxn1 mice to mimic breast cancer metastasis and collected myeloid cells using fluorescence activated cell sorting (FACS) from three unaffected and three metastatic mouse brains. We then performed single-cell RNA sequencing on >50,000 cells and identified cell states enhanced in metastatic brains. Notably, we find subpopulations of microglia (the resident macrophages of the brain) with increased antigen presentation and type 1 interferon response which we hypothesized would mount an anti-tumor response through interactions with T cells in an immune competent setting. We validated that these microglia population enrichments exist on the protein level as well as in immunocompetent mouse models of BCBM and demonstrated the generalizability of our findings using the MITRG humanized mouse model and publicly available patient datasets. We have also collected preliminary data which suggests that microglial depletion results in increased tumor engraftment and infiltration of suppressive T cells into the brain microenvironment, supporting our hypothesized anti-tumoral role for microglia. Thus, our ongoing work hopes to characterize the functional interactions between microglia and T cells to establish their respective contributions to tumor rejection in BCBM.