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Targeting the HSP47-collagen axis inhibits brain metastasis by reversing M2 microglial polarization and restoring
Li Wang1, Cuiying Li1, Hongchao Zhan1
1Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China.
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.
Insights
Heat shock protein 47 (HSP47) drives brain metastasis by promoting an immunosuppressive environment. Inhibiting HSP47 restores anti-tumor immunity and enhances immunotherapy efficacy for brain tumors.
Area of Science:
- Oncology
- Immunology
- Cancer Metastasis
Background:
- Brain metastases (BrMs) are a major cause of cancer mortality.
- BrMs present an immunosuppressive microenvironment, limiting immunotherapy effectiveness.
- The mechanisms driving BrM immunosuppression are not fully understood.
Purpose of the Study:
- To elucidate the role of heat shock protein 47 (HSP47) in brain metastasis.
- To investigate how HSP47 contributes to the immunosuppressive microenvironment in BrMs.
- To evaluate therapeutic strategies targeting the HSP47-collagen axis.
Main Methods:
- Investigated HSP47 upregulation in tumor cells and its effect on the brain microenvironment.
- Analyzed microglial polarization and CD8+ T cell responses in BrM models.
- Utilized a specific inhibitor (Col003) targeting HSP47-collagen interactions.
- Assessed the efficacy of HSP47 inhibition combined with anti-PD-L1 immunotherapy in mice.
Main Results:
- HSP47 upregulation in tumor cells promotes brain metastatic colonization and outgrowth.
- HSP47 induces M2 microglial polarization via the α2β1 integrin/NF-κB pathway, suppressing anti-tumor immunity.
- Microglial depletion reverses HSP47-induced CD8+ T cell inactivation and reduces BrM.
- Col003 treatment restores anti-tumor immunity and enhances anti-PD-L1 efficacy in BrM models.
Conclusions:
- HSP47 is a key driver of M2 microglial polarization and immunosuppression in brain metastases.
- Targeting the HSP47-collagen axis is a promising therapeutic strategy for brain tumors.
- Blocking HSP47 can overcome immunotherapy resistance in brain metastatic disease.
