Defining RIPK3-dependent tumor immunosurveillance functions of microglia in brain metastasis 3337

Abstract Description Metastatic breast cancer accounts for the majority of breast cancer-related deaths. The central nervous system (CNS) is a common site of metastasis that is associated with particularly poor survival prognoses. Metastasis is initiated by disseminated tumor cells (DTCs) that exit the primary tumor, seed distal tissues, evade immunosurveillance, and assume a dormant phenotype before eventually proliferating to form clinically apparent metastases. Notably, the molecular mechanisms underlying effective immunosurveillance of DTCs by CNS-resident macrophages termed microglia remain poorly understood. To investigate signaling pathways involved in microglial activation early on during CNS metastasis, we transcriptionally profiled tumor-targeting vs. non-targeting microglia sorted from the brains of immunocompetent mice seeded with dormant D2.OR mammary carcinoma cells. We found that tumor-targeting microglia exhibit a beneficial inflammatory phenotype characterized by upregulation of receptor-interacting protein kinase 3 (RIPK3) and RIPK3-dependent target genes, which are known to drive protective inflammatory signaling in numerous cell types. Our next steps will determine how RIPK3 activation influences microglial functions in the context of microglial phagocytosis of DTCs, potentially revealing novel therapeutic targets that could be leveraged to restore microglial immunosurveillance and prevent the outgrowth of DTCs into lethal CNS metastases. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)