UC Irvine

Breast cancer brain metastasis (BCBM) is an increasingly prevalent clinical problem, due largely to improvements in treatment of primary tumors. Incidence of BCBM is rapidly fatal and difficult to treat, owing to the relative impermeability of the blood-brain barrier (BBB) to standard-of-care treatments and restrictions on the influx of peripheral immune cells during tumor initiation. As the resident macrophage and predominant immune cell of the central nervous system (CNS), microglia are poised to be the first responders to metastatic tumor infiltration, however an accumulating body of literature implies that microglia facilitate tumor growth in the CNS and brain parenchyma. In the following studies, we employ single-cell RNA sequencing (scRNAseq), spatial immunophenotying and flow cytometry on murine models of BCBM to interrogate the CNS immune microenvironment during tumor initiation to evaluate the tumoricidal potential of microglia and evaluate modalities for treatment of intracranial metastases. We identify the emergence of a pro-inflammatory program in microglia upon incidence of BCBM consistent with the canonical activity of a tumoricidal macrophage. We subsequently demonstrate that microglia upregulate antigen presentation (AP) machinery, and this activity is largely dependent on the infiltration of lymphocytes from the periphery. Finally, we evaluate the impact of agonistic anti-CD40 antibody on AP activity and the capacity to clear BCBM lesions.