Targeting the HSP47-collagen axis inhibits brain metastasis by reversing M2 microglial polarization and restoring anti-tumor immunity
Li Wang, Cuiying Li, Hongchao Zhan, Shangbiao Li, Kunlin Zeng, Chang Xu, Yulong Zou, Yuxin Xie, Ziling Zhan, Shengqi Yin, Yu Zeng, Xiaoxia Chen, Guangzhao Lv, Zelong Han, Dexiang Zhou, Dexiang Zhou, Dong Zhou, Dong Zhou, Yong Yang, Aidong Zhou
Abstract
Brain metastases (BrMs) are the leading cause of death in patients with solid cancers. BrMs exhibit a highly immunosuppressive milieu and poor response to immunotherapies; however, the underlying mechanism remains largely unclear. Here, we show that upregulation of HSP47 in tumor cells drives metastatic colonization and outgrowth in the brain by creating an immunosuppressive microenvironment. HSP47-mediated collagen deposition in the metastatic niche promotes microglial polarization to the M2 phenotype via the α2β1 integrin/nuclear factor κB pathway, which upregulates the anti-inflammatory cytokines and represses CD8 + T cell anti-tumor responses. Depletion of microglia reverses HSP47-induced inactivation of CD8 + T cells and abolishes BrM. Col003, an inhibitor disrupting HSP47-collagen association restores an anti-tumor immunity and enhances the efficacy of anti-PD-L1 immunotherapy in BrM-bearing mice. Our study supports that HSP47 is a critical determinant of M2 microglial polarization and immunosuppression and that blocking the HSP47-collagen axis represents a promising therapeutic strategy against brain metastatic tumors.