2. Academic Validation
  3. Targeting the HSP47-collagen axis inhibits brain metastasis by reversing M2 microglial polarization and restoring anti-tumor immunity

Targeting the HSP47-collagen axis inhibits brain metastasis by reversing M2 microglial polarization and restoring anti-tumor immunity

  • Cell Rep Med. 2024 May 21;5(5):101533. doi: 10.1016/j.xcrm.2024.101533.
Li Wang 1,  Cuiying Li 1,  Hongchao Zhan 1,  Shangbiao Li 2,  Kunlin Zeng 1,  Chang Xu 1,  Yulong Zou 1,  Yuxin Xie 1,  Ziling Zhan 1,  Shengqi Yin 1,  Yu Zeng 1,  Xiaoxia Chen 1,  Guangzhao Lv 3,  Zelong Han 4,  Dexiang Zhou 3,  Dong Zhou 5,  Yong Yang 6,  Aidong Zhou 7
Affiliations

Affiliations

  • 1 Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China.
  • 2 Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China; Department of Radiation Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou 510515, China.
  • 3 Department of Neurosurgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510000, China.
  • 4 Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
  • 5 Department of Neurosurgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510000, China. Electronic address: zhoudong5413@163.com.
  • 6 Department of Neurosurgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510000, China. Electronic address: yangyong@gdph.org.cn.
  • 7 Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China; Department of Neurosurgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510000, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Southern Medical University, Guangzhou 510515, China. Electronic address: aidern0927@smu.edu.cn.
PMID: 38744278 DOI: 10.1016/j.xcrm.2024.101533
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.

Keywords

HSP47; anti-tumor immunity; brain metastases; collagen; microglia.

Figures
Products