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

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

  • Cell Metab. 2021 Oct 5;33(10):2040-2058.e10. doi: 10.1016/j.cmet.2021.09.002.
Samantha M Morrissey 1,  Fan Zhang 2,  Chuanlin Ding 3,  Diego Elias Montoya-Durango 3,  Xiaoling Hu 3,  Chenghui Yang 4,  Zhen Wang 5,  Fang Yuan 6,  Matthew Fox 7,  Huang-Ge Zhang 8,  Haixun Guo 9,  David Tieri 10,  Maiying Kong 11,  Corey T Watson 10,  Robert A Mitchell 3,  Xiang Zhang 6,  Kelly M McMasters 3,  Jian Huang 5,  Jun Yan 12
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY, USA; Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.
  • 2 Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA; Jiangxi Provincial Children's Hospital, Jiangxi, Nanchang, China.
  • 3 Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.
  • 4 Department of Breast Surgery, Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Cancer Research Institute of Zhejiang University, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, China; Department of Breast Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
  • 5 Department of Breast Surgery, Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Cancer Research Institute of Zhejiang University, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, China.
  • 6 Department of Chemistry, University of Louisville, Louisville, KY, USA.
  • 7 Department of Cardiovascular and Thoracic Surgery, University of Louisville School of Medicine, Louisville, KY, USA.
  • 8 Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY, USA.
  • 9 Department of Radiology, University of Louisville School of Medicine, Louisville, KY, USA.
  • 10 Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, USA.
  • 11 Department of Bioinformatics and Biostatistics, University of Louisville, School of Medicine, Louisville, KY, USA.
  • 12 Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY, USA; Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA. Electronic address: jun.yan@louisville.edu.
PMID: 34559989 DOI: 10.1016/j.cmet.2021.09.002
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.

Keywords

NF-kB; PD-L1; exosomes; glycolysis; immunosuppression; lactate; metastasis.

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