Tumor-derived exosomes drive immunosuppressive macrophages in a pre-metastatic niche through glycolytic dominant metabolic reprogramming

被引:351
|
作者
Morrissey, Samantha M. [1 ,2 ]
Zhang, Fan [2 ,3 ]
Ding, Chuanlin [2 ]
Montoya-Durango, Diego Elias [2 ]
Hu, Xiaoling [2 ]
Yang, Chenghui [4 ,5 ]
Wang, Zhen [4 ]
Yuan, Fang [6 ]
Fox, Matthew [7 ]
Zhang, Huang-ge [1 ]
Guo, Haixun [8 ]
Tieri, David [9 ]
Kong, Maiying [10 ]
Watson, Corey T. [9 ]
Mitchell, Robert A. [2 ]
Zhang, Xiang [6 ]
McMasters, Kelly M. [2 ]
Huang, Jian [4 ]
Yan, Jun [1 ,2 ]
机构
[1] Univ Louisville, Sch Med, Dept Microbiol & Immunol, Louisville, KY 40292 USA
[2] Univ Louisville, Brown Canc Ctr, Hiram C Polk Jr MD Dept Surg, Div Immunotherapy,Immunooncol Program,Sch Med, Louisville, KY 40292 USA
[3] Jiangxi Prov Childrens Hosp, Nanchang, Jiangxi, Peoples R China
[4] Zhejiang Univ, Canc Res Inst Zhejiang Univ, Affiliated Hosp 2,Sch Med, Dept Breast Surg,Key Lab Tumor Microenvironm & Im, Hangzhou, Zhejiang, Peoples R China
[5] Wenzhou Med Univ, Affiliated Hosp 1, Dept Breast Surg, Wenzhou, Peoples R China
[6] Univ Louisville, Dept Chem, Louisville, KY 40292 USA
[7] Univ Louisville, Dept Cardiovasc & Thorac Surg, Sch Med, Louisville, KY USA
[8] Univ Louisville, Dept Radiol, Sch Med, Louisville, KY USA
[9] Univ Louisville, Dept Biochem & Mol Genet, Sch Med, Louisville, KY USA
[10] Univ Louisville, Sch Med, Dept Bioinformat & Biostat, Louisville, KY USA
基金
中国国家自然科学基金;
关键词
SATURATED FATTY-ACIDS; PD-L1; EXPRESSION; CELLS; BIOLOGY; POLARIZATION; SUPPRESSION; ACTIVATION; SURVIVAL; PATHWAY;
D O I
10.1016/j.cmet.2021.09.002
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
One of the defining characteristics of a pre-metastatic niche, a fundamental requirement for primary tumor metastasis, is infiltration of immunosuppressive macrophages. How these macrophages acquire their phenotype remains largely unexplored. Here, we demonstrate that tumor-derived exosomes (TDEs) polarize macrophages toward an immunosuppressive phenotype characterized by increased PD-L1 expression through NF-kB-dependent, glycolytic-dominant metabolic reprogramming. TDE signaling through TLR2 and NF-KB leads to increased glucose uptake. TDEs also stimulate elevated NOS2, which inhibits mitochondrial oxidative phosphorylation resulting in increased conversion of pyruvate to lactate. Lactate feeds back on NF-KB, further increasing PD-L1. Analysis of metastasis-negative lymph nodes of non-small-cell lung cancer patients revealed that macrophage PD-L1 positively correlates with levels of GLUT-1 and vesicle release gene YKT6 from primary tumors. Collectively, our study provides a novel mechanism by which macrophages within a pre-metastatic niche acquire their immunosuppressive phenotype and identifies an important link among exosomes, metabolism, and metastasis.
引用
收藏
页码:2040 / +
页数:30
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