Hypoxia-induced tumor exosomes promote M2-like macrophage polarization of infiltrating myeloid cells and microRNA-mediated metabolic shift

• Published in: Oncogene Vol. 38; no. 26; pp. 5158 - 5173
• Main Authors: Park, Jung Eun, Dutta, Bamaprasad, Tse, Shun Wilford, Gupta, Nikhil, Tan, Chee Fan, Low, Jee Keem, Yeoh, Kheng Wei, Kon, Oi Lian, Tam, James P., Sze, Siu Kwan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2019; Nature Publishing Group
• Subjects: 13/31; 14/63; 38/77; 631/250/580; 631/67/2327; 631/67/327; 64/60; 82/47; A549 Cells; AKT protein; Angiogenesis; Animals; Apoptosis; Bone marrow; Cancer; Cell Biology; Cell Movement; Cell Polarity; Cells, Cultured; Chemistry, Analytic; Chemokines; Chemotaxis, Leukocyte - physiology; Development and progression; Exosomes; Exosomes - metabolism; Exosomes - physiology; Genetic aspects; Health aspects; Human Genetics; Humans; Hypoxia; Immunomodulation; Immunosuppression; Insulin; Internal Medicine; Macrophage colony-stimulating factor; Macrophages; Macrophages - physiology; Male; Medicine; Medicine & Public Health; Metabolome - physiology; Metastases; Mice; Mice, Inbred C57BL; MicroRNA; MicroRNAs - physiology; miRNA; Monocyte chemoattractant protein 1; Monocytes; Myeloid cells; Myeloid Cells - pathology; Myeloid Cells - physiology; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - pathology; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - pathology; Oncology; Oxidative Phosphorylation; Phosphorylation; Polarization; Proteomics; Quantitative; RAW 264.7 Cells; Signal transduction; TOR protein; Tumor cells; Tumor Hypoxia - physiology; Tumor-infiltrating lymphocytes
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/s41388-019-0782-x

Developing tumors rapidly outgrow their oxygen supply and are subject to hypoxia, which stimulates hypersecretion of tumor-derived exosomes that promote angiogenesis, metastasis, and immunosuppression, but the molecular mediators of these pathological effects remain poorly defined. Using quantitative proteomics, we identified that exosomes produced by hypoxic tumor cells are highly enriched in immunomodulatory proteins and chemokines including CSF-1, CCL2, FTH, FTL, and TGFβ. Modeling exosome effects on tumor-infiltrating immune cells, we observed a potent ability of these hypoxia-induced vesicles to influence macrophage recruitment and promote M2-like polarization both in vitro and in vivo. In addition, hypoxic, but not normoxic, tumor exosomes enhanced oxidative phosphorylation in bone marrow-derived macrophages via transfer of let-7a miRNA, resulting in suppression of the insulin-Akt-mTOR signaling pathway. Together, these data demonstrate that hypoxia promotes tumor secretion of biomolecule-loaded exosomes that can modify the immunometabolic profile of infiltrating monocyte-macrophages to better evade host immunity and enhance tumor progression.