CircADAMTS12 Inhibits the Anti-Tumor Activity of Microglia to Enable Metastatic Colonization in the Brain

Abstract

Microglia promote anti-tumor immunity and suppress breast-to-brain metastasis (B2BM), which is a lethal complication in breast cancer patients without effective therapeutic options. Unraveling the molecular mechanism by which B2BM cancer cells evade microglial-mediated anti-tumor immunity in the brain could reveal potential treatment strategies. Here, we showed that gain of expression of the circular RNA circADAMTS12 in cancer cells supported breast cancer metastatic colonization in the brain by suppressing the anti-tumor activity of microglia. Mechanistically, circADAMTS12 in cancer cells induced anti-inflammatory M2-like polarization of microglia and upregulated PD-L1 expression in both microglia and cancer cells. Furthermore, the elevated PD-L1 in cancer cells inhibited the phagocytic activity of microglia. Both targeting circADAMTS12 and PD-L1 blockade effectively suppressed metastatic brain colonization in T cell deficient nude mice, while targeting circADAMTS12 synergized with PD-L1 blockade to block brain metastasis in immunocompetent wild-type mice. These findings suggest that circADAMTS12 suppresses microglial-mediated anti-tumor immunity to support metastatic colonization of breast cancer cells in the brain.