Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, 107 Wenhua Western Road, Jinan 250012, Shandong, China; Shandong Key Laboratory of Brain Function Remodeling, Jinan 250012, Shandong, China.
Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, 107 Wenhua Western Road, Jinan 250012, Shandong, China; Department of Neurology, Loma Linda University Health, Loma Linda, CA 92350, USA.
Mol Ther. 2021 Dec 1;29(12):3449-3464. doi: 10.1016/j.ymthe.2021.06.023. Epub 2021 Jul 2.
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.
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发挥关键作用。髓系来源的抑制性细胞（MDSCs）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 MDSCs 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。胶质瘤细胞可以通过外泌体的分泌与免疫细胞进行系统性通讯，外泌体中包含 microRNAs（miRNAs）。利用外泌体的 miRNA 测序，我们鉴定到 miR-1246 在胶质瘤来源的外泌体和从胶质瘤患者脑脊液（CSF）中分离的外泌体中富集。我们证明了 miR-1246 通过双特异性磷酸酶 3（DUSP3）/细胞外信号调节激酶（ERK）依赖性方式驱动 MDSC 的分化和激活。此外，术后 CSF 外泌体 miR-1246 的表达与胶质瘤的复发率有关。缺氧是脑胶质瘤微环境的一个公认特征，通过增强 miR-1246 转录和通过上调 POU 类 5 同源框 1（POU5F1）和异质核核糖核蛋白 A1（hnRNPA1）的选择性包装，增加胶质瘤来源的外泌体中的 miR-1246 水平。重要的是，我们确定了 2-甲氧基雌二醇的一种作用机制，2-甲氧基雌二醇是一种微管抑制剂，目前正在临床试验中用于治疗脑胶质瘤。2-甲氧基雌二醇通过抑制缺氧驱动的胶质瘤细胞中外泌体 miR-1246 的表达和 MDSC 中的 PD-L1 表达来抑制 MDSC 的激活。
