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

Samantha M. Morrissey, Fan Zhang, Chuanlin Ding, Diego Elias Montoya-Durango, Xiaoling Hu, Chenghui Yang, Zhen Wang, Fang Yuan, Matthew Fox, Huang ge Zhang, Haixun Guo, David Tieri, Maiying Kong, Corey T. Watson, Robert A. Mitchell, Xiang Zhang, Kelly M. McMasters, Jian Huang, Jun Yan

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

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-κB 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-κB, 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.

Original languageEnglish
Pages (from-to)2040-2058.e10
JournalCell Metabolism
Volume33
Issue number10
DOIs
StatePublished - 5 Oct 2021
Externally publishedYes

Keywords

  • NF-kB
  • PD-L1
  • exosomes
  • glycolysis
  • immunosuppression
  • lactate
  • metastasis

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