共 41 条
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.
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页码:2040 / +
页数:30
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