Exosomal miR-1246 from glioma patient body fluids drives the differentiation and activation of myeloid-derived suppressor cells
Exosomal miR-1246 from glioma patient body fluids drives the differentiation and activation of myeloid-derived suppressor cells
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神经胶质瘤患者体液中的外泌体 miR-1246 驱动骨髓源性抑制细胞的分化和激活
DOI：
10.1016/j.ymthe.2021.06.023
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发表时间：
2021-12-01
影响因子：
12.4
通讯作者：
Li, Gang
中科院分区：
文献类型：
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作者：
Qiu, Wei;Guo, Xiaofan;Li, Gang
胶质瘤是一种异质性细胞环境，其中免疫细胞在肿瘤进展中起关键作用。髓源性抑制细胞（MDSC）有助于胶质瘤免疫抑制微环境的形成;然而，胶质瘤细胞如何与MDSC相互作用以及这种相互作用如何影响其他免疫细胞的功能尚不清楚。神经胶质瘤细胞可以通过分泌含有微小RNA（miRNA）的外泌体与免疫细胞进行系统性通信。利用外来体的miRNA测序，我们鉴定了miR-1246在胶质瘤来源的外来体和从胶质瘤患者的脑脊液（CSF）分离的外来体中的富集。我们证明了miR-1246以双特异性磷酸酶3（DUSP 3）/细胞外信号调节激酶（ERK）依赖的方式驱动MDSC的分化和活化。此外，发现术后CSF外泌体miR-1246表达与胶质瘤复发率相关。缺氧是胶质母细胞瘤微环境的一个公认特征，通过上调POU 5类同源框1（POU 5 F1）和异质核核糖核蛋白A1（hnRNPA 1）增强miR-1246转录和选择性包装，增加胶质瘤来源外泌体中miR-1246的水平。重要的是，我们确定了2-甲氧基紫杉醇的机制，2-甲氧基紫杉醇是一种微管抑制剂，目前正在进行胶质母细胞瘤的临床试验。2-甲氧基紫杉醇通过抑制胶质瘤细胞中低氧驱动的外泌体miR-1246表达和MDSC中的PD-L1表达来抑制MDSC活化。
Glioma is a heterogeneous cellular environment in which immune cells play critical roles in tumor progression. Myeloid derived suppressor cells (MDSCs) contribute to the formation of the immunosuppressive microenvironment of glioma; however, how glioma cells interact with MDSCs and how this interaction affects the function of other immune cells are unclear. Glioma cells can systemically communicate with immune cells via the secretion of exosomes, which contain microRNAs (miRNAs). Leveraging miRNA sequencing of exosomes, we identified enrichment of miR-1246 in glioma-derived exosomes and exosomes isolated from the cerebrospinal fluid (CSF) of glioma patients. We demonstrated that miR-1246 drives the differentiation and activation of MDSCs in a dual specificity phosphatase 3 (DUSP3)/extracellular signal-regulated kinase (ERK)-dependent manner. In addition, postoperative CSF exosomal miR-1246 expression was found to be associated with the glioma recurrence rate. Hypoxia, a well-recognized feature of the glioblastoma microenvironment, increased miR-1246 levels in glioma-derived exosomes by enhancing miR-1246 transcription and selective packaging via upregulation of POU class 5 homeobox 1 (POU5F1) and heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1). Importantly, we identified a mechanism of 2-methoxyestradiol, a microtubule inhibitor currently undergoing clinical trials for glioblastoma. 2-Methoxyestradiol suppresses MDSC activation by inhibiting hypoxia-driven exosomal miR-1246 expression in glioma cells and PD-L1 expression in MDSCs.