1. Academic Validation
  2. 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

  • Mol Ther. 2021 Dec 1;29(12):3449-3464. doi: 10.1016/j.ymthe.2021.06.023.
Wei Qiu 1 Xiaofan Guo 2 Boyan Li 1 Jian Wang 3 Yanhua Qi 1 Zihang Chen 1 Rongrong Zhao 1 Lin Deng 1 Mingyu Qian 1 Shaobo Wang 1 Zongpu Zhang 1 Qindong Guo 1 Shouji Zhang 1 Ziwen Pan 1 Shulin Zhao 1 Hao Xue 4 Gang Li 5
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 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 Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway.
  • 4 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. Electronic address: [email protected].
  • 5 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. Electronic address: [email protected].
Abstract

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.

Keywords

2-methoxyestradiol; MDSC; cerebrospinal fluid; exosomes; glioma; miR-1246.

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