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

被引：13

作者：

Wang, Li ^{[1
]}

Li, Cuiying ^{[1
]}

Zhan, Hongchao ^{[1
]}

Li, Shangbiao ^{[1
,3
]}

Zeng, Kunlin ^{[1
]}

Xu, Chang ^{[1
]}

Zou, Yulong ^{[1
]}

Xie, Yuxin ^{[1
]}

Zhan, Ziling ^{[1
]}

Yin, Shengqi ^{[1
]}

Zeng, Yu ^{[1
]}

Chen, Xiaoxia ^{[1
]}

Lv, Guangzhao ^{[2
]}

Han, Zelong ^{[4
]}

Zhou, Dexiang ^{[2
]}

Zhou, Dong ^{[2
]}

Yang, Yong ^{[2
]}

Zhou, Aidong ^{[1
,2
,5
]}

机构：

[1] Southern Med Univ, Sch Basic Med Sci, Dept Cell Biol, Guangzhou 510515, Peoples R China

[2] Southern Med Univ, Guangdong Prov Peoples Hosp, Guangdong Acad Med Sci, Dept Neurosurg, Guangzhou 510000, Peoples R China

[3] Southern Med Univ, Zhujiang Hosp, Dept Radiat Oncol, Guangzhou 510515, Peoples R China

[4] Southern Med Univ, Nanfang Hosp, Dept Gastroenterol, Guangzhou 510515, Peoples R China

[5] Southern Med Univ, Guangdong Prov Key Lab Mol Tumor Pathol, Guangzhou 510515, Peoples R China

来源：

CELL REPORTS MEDICINE | 2024年 / 5卷 / 05期

基金：

中国国家自然科学基金;

关键词：

CANCER; CHAPERONE; CELLS;

D O I：

10.1016/j.xcrm.2024.101533

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 a2b1 integrin/nuclear factor kB 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 HSP47collagen axis represents a promising therapeutic strategy against brain metastatic tumors.

引用

页数：22

共 44 条

[1] Brain metastases [J].