Microglial reprogramming enhances antitumor immunity and immunotherapy response in melanoma brain metastases

Melanoma is one of the tumor types with the highest risk of brain metastasis. However, the biology of melanoma brain metastasis and the contribution of the brain immune microenvironment to the responses to therapies remain insufficiently characterized. By using preclinical models and single-cell transcriptomics, we identify a mechanism to promote antitumor immunity in melanoma brain metastasis. We show that activation of the Rela/NF-kB pathway in microglia promotes melanoma brain metastasis and that targeting this pathway elicits microglia reprogramming towards a proinflammatory phenotype that enhances antitumor immunity and reduces brain metastatic burden. Additionally, proinflammatory microglial markers in melanoma brain metastasis correlate with better responses to immune checkpoint inhibitors in patients and we show that Rela/NF-kB targeting improves responses to these therapies in the brain. Thus, we propose targeting Rela/NF-kB in activated microglia as a strategy to promote antitumor immunity and responses to immune checkpoint inhibitors in melanoma brain metastasis. Single cell RNA-seq Data Analysis of CD45+/CX3CR1+ immune cells isolated in NRAS* MBMs generated in Rela WT and Rela cKO mice