Targeting metabolic vulnerabilities attenuates melanoma brain metastasis through immunomodulatory mechanisms

Metastasis is a multistep process involving not only tumor cell-autonomous changes, but also tumor-driven rewiring of the microenvironment at the metastatic site in order to establish a hospitable metastatic niche. Such reprogramming of the microenvironment is highly organ-specific and associated with disease prognosis. Melanomas frequently metastasize to the brain and patients with brain metastasis have the highest mortality rates. Two important features of brain metastasis are neuroinflammation that precedes metastasis, and the unique metabolic requirements in the brain that necessitate metastasizing cells to acquire enhanced fatty acid synthesis and oxidation capabilities in order to adapt to the brain microenvironment. Metastatic cells also uptake metabolites from astrocytes within the brain microenvironment to sustain their survival. Our study focused on targeting brain metastasis by repurposing existing therapies to prevent tumor-promoting inflammation and simultaneously decrease availability of metabolites necessary for survival within the brain niche. Using mouse models of experimental brain metastasis, we tested the potential therapeutic effect of Atorvastatin, a cholesterol-lowering drug, on brain metastasis. We show that statin treatment significantly reduced brain metastatic burden, as assessed by MRI and flow cytometry, and improved survival in mice. Mechanistically, attenuation of brain metastasis by statins was associated with decreased myeloid cell recruitment and increased T cell infiltration, within the brain, alongside similar changes in systemic immune populations, suggesting alleviation of tumor-promoting inflammation. CyTOF analysis of the immune compartment revealed decreased expression of immune checkpoint markers, indicative of immune reprogramming. Proteomics and gene set enrichment analysis of resident and infiltrating brain cell populations isolated from statin-treated mouse brains, suggested changes in metabolic pathways and immune reactivation. Further, proteome analysis of tumor cells revealed that statins attenuate oncogenic signaling & induce apoptosis in melanoma cells, uncovering melanoma cell-intrinsic effects of statins. In vitro studies further validated the inhibitory effects of statins on brain-tropic melanoma cells and on rewiring of astrocyte gene expression. Taken together, our findings implicate statins as a potential therapeutic strategy to prevent/inhibit brain metastasis.