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

Cell metabolism 2021 Oct 05

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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. Copyright © 2021 Elsevier Inc. All rights reserved.

Citation

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. Tumor-derived exosomes drive immunosuppressive macrophages in a pre-metastatic niche through glycolytic dominant metabolic reprogramming. Cell metabolism. 2021 Oct 05;33(10):2040-2058.e10