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

Abstract

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.

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Acknowledgements

This work is in part supported by grants from the Singapore Ministry of Education (MOE2014-T2-2-043, MOE2016-T2-2-018, and MOE2016-T3-1-003) and the National Medical Research Council of Singapore (NMRC-OF-IRG-0003-2016).

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JEP designed and performed the experiments, analyzed the data, and wrote the paper; BD performed the exosome TMT proteomics experiments and analyzed the data; SWT and NG performed animal experiments; CFT performed exosome preparation and analysis; and JKL, KWY, OLK, and JPT contributed to reagents and discussion; SSK conceived, designed, supervised the project, and revised the manuscript. All co-authors contributed to the revision of the manuscript.

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Correspondence to Jung Eun Park or Siu Kwan Sze.

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Park, J.E., Dutta, B., Tse, S.W. et al. Hypoxia-induced tumor exosomes promote M2-like macrophage polarization of infiltrating myeloid cells and microRNA-mediated metabolic shift. Oncogene 38, 5158–5173 (2019). https://doi.org/10.1038/s41388-019-0782-x

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