UC Irvine

Breast cancer brain metastasis (BCBM) is a lethal disease with no effective treatment options and limited experimental models. BCBMs are densely infiltrated by activated macrophages, but their origin, function and potential for therapeutic targeting are controversial. We used single-cell RNA-sequencing to investigate the role of brain-resident microglia in mouse and humanized models of BCBM. We find that mouse and human microglia directly interface with metastatic cells and mount a robust pro-inflammatory response. This is associated with upregulation of type I and II interferon responses, antigen presentation machinery cytokine and exome secretion and expansion of T and natural killer (NK) lymphocytes that control tumor outgrowth. Functional studies show that microglia depleted animals display decreased survival, increased metastasis, and impaired T and NK cell response to BCBM. This demonstrates the important tumor suppressive function of microglia during BCBM initiation.