Immunosuppressive effects of hypoxia-induced glioma exosomes through myeloid-derived suppressor cells via the miR-10a/Rora and miR-21/Pten Pathways
Immunosuppressive effects of hypoxia-induced glioma exosomes through myeloid-derived suppressor cells via the miR-10a/Rora and miR-21/Pten Pathways
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缺氧诱导的胶质瘤外泌体通过骨髓源性抑制细胞通过 miR-10a/Rora 和 miR-21/Pten 途径产生免疫抑制作用
DOI：
10.1038/s41388-018-0261-9
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发表时间：
2018-08-02
期刊：
影响因子：
8
通讯作者：
Li, Gang
中科院分区：
文献类型：
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作者：
Guo, Xiaofan;Qiu, Wei;Li, Gang
虽然在神经胶质瘤患者中已充分记录了髓源性抑制细胞（MDSC）介导的免疫抑制环境，但MDSC发育和激活的机制尚未明确定义。在这里，我们阐明了胶质瘤源性外泌体（GDE）在增强MDSC途径中的作用。我们分离了常氧刺激和低氧刺激的GDE，并研究了它们在体内和体外诱导MDSC的能力。采用脾和骨髓MDSC比例（流式细胞术）和活性氧（ROS）、过氧化物酶活性、一氧化氮（NO）、T细胞增殖和免疫抑制细胞因子（IL-10和TGF-β，ELISA）水平的分析来评估MDSC扩增和功能能力。我们还对两种类型的GDE进行了microRNA（miRNA）测序分析，以找到可能介导MDSC发育和激活的miRNA。还研究了MDSC中的GDE miRNA细胞内信号传导。缺氧促进GDEs的分泌，小鼠MDSCs可摄取GDEs。低氧刺激的GDE比N-GDE具有更强的诱导MDSC的能力。GDE中miR-10a和miR-21的低氧诱导表达通过靶向RAR相关孤儿受体α（RORA）和磷酸酶和张力蛋白同源物（PTEN）介导GDE诱导的MDSC扩增和活化。与接种正常胶质瘤细胞的小鼠相比，接种miR-10a或miR-21敲除胶质瘤细胞的小鼠产生更少的MDSC。这些数据阐明了胶质瘤细胞通过外来体影响MDSC的分化和活化的机制，并证明了局部胶质瘤缺氧如何影响整个肿瘤免疫环境。
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.