Targeting the HSP47-collagen axis inhibits brain metastasis by reversing M2 microglial polarization and restoring anti-tumor immunity.
Cell Rep Med
; 5(5): 101533, 2024 May 21.
Article
de En
| MEDLINE
| ID: mdl-38744278
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 α2ß1 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.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Tumeurs du cerveau
/
Collagène
/
Microglie
/
Lymphocytes T CD8/
/
Protéines de choc thermique HSP47
Limites:
Animals
/
Female
/
Humans
Langue:
En
Journal:
Cell Rep Med
/
Cell reports medicine
Année:
2024
Type de document:
Article
Pays d'affiliation:
Chine
Pays de publication:
États-Unis d'Amérique