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Immunosuppressive effects of hypoxia-induced glioma exosomes through myeloid-derived suppressor cells via the miR-10a/Rora and miR-21/Pten Pathways

Oncogenevolume 37pages42394259 (2018) | Download Citation

Abstract

While immunosuppressive environments mediated by myeloid-derived suppressor cells (MDSCs) have been well documented in glioma patients, the mechanisms of MDSC development and activation have not been clearly defined. Here, we elucidated a role for glioma-derived exosomes (GDEs) in potentiating an MDSC pathway. We isolated normoxia-stimulated and hypoxia-stimulated GDEs and studied their MDSC induction abilities in vivo and in vitro. Analyses of spleen and bone marrow MDSC proportions (flow cytometry) and reactive oxygen species (ROS), arginase activity, nitric oxide (NO), T-cell proliferation and immunosuppressive cytokine (IL-10 and TGF-β, ELISA) levels were used to assess MDSC expansion and functional capacity. We also performed microRNA (miRNA) sequencing analysis of two types of GDEs to find miRNAs that potentially mediate the development and activation of MDSCs. GDE miRNA intracellular signaling in MDSCs was also studied. Hypoxia promoted the secretion of GDEs, and mouse MDSCs could uptake GDEs. Hypoxia-stimulated GDEs had a stronger ability to induce MDSCs than N-GDEs. The hypoxia-inducible expression of miR-10a and miR-21 in GDEs mediated GDE-induced MDSC expansion and activation by targeting RAR-related orphan receptor alpha (RORA) and phosphatase and tensin homolog (PTEN). Mice inoculated with miR-10a or miR-21 knockout glioma cells generated fewer MDSCs than those inoculated with normal glioma cells. These data elucidated a mechanism by which glioma cells influence the differentiation and activation of MDSCs via exosomes and demonstrated how local glioma hypoxia affects the entirety of tumor immune environments.

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Additional information

First author’s name: Xiaofan Guo and Wei Qiu.

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Acknowledgements

This work was supported by of the National Natural Science Foundation of China, Department of Science& Technology of Shandong Province, Brain Science Research Institute of Shandong University, Department of Neurosurgery of Qilu Hospital of Shandong University. We thank Professor Xun Qu for helpful comments and advice on this work.

Funding

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81101594; 81372719; 81172403; 81300510; 81402077; 81571284; 91542115; 81702468), National Natural Science Foundation of Shandong Province of China (No. 2017CXGC1203) and Taishan Scholars of Shandong Province of China (No. ts201511093).

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Affiliations

  1. Brain Science Research Institute, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong Province, 250012, P.R. China

    • Xiaofan Guo
    • , Wei Qiu
    • , Mingyu Qian
    • , Shaobo Wang
    • , Zongpu Zhang
    • , Xiao Gao
    • , Zihang Chen
    • , Hao Xue
    •  & Gang Li
  2. Department of Neurosurgery, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Jinan, Shandong Province, 250012, P.R. China

    • Qinglin Liu
    • , Hao Xue
    •  & Gang Li

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The authors declare that they have no conflict of interest.

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Correspondence to Hao Xue or Gang Li.

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DOI

https://doi.org/10.1038/s41388-018-0261-9