Glioma exosomes mediate the expansion and function of myeloid‐derived suppressor cells through microRNA‐29a/Hbp1 and microRNA‐92a/Prkar1a pathways

Abstract

Myeloid‐derived suppressor cells (MDSCs) play a pivotal role in mediating the formation of an immunosuppressive environment and assisting tumors in evading the host immune response. However, the mechanism through which tumors manipulate the differentiation and function of MDSCs remains unclear. Here, we report that hypoxia‐induced glioma cells can stimulate the differentiation of functional MDSCs by transferring exosomal miR‐29a and miR‐92a to MDSCs. Our results showed that glioma‐derived exosomes (GEXs) can enhance the differentiation of functional MDSCs both in vitro and in vivo, and hypoxia‐induced GEXs (H‐GEXs) demonstrated a stronger MDSCs induction ability than did normoxia‐induced GEXs (N‐GEXs). A subsequent miRNA sequencing analysis of N‐GEXs and H‐GEXs revealed that hypoxia‐induced exosomal miR‐29a and miR‐92a expression induced the propagation of MDSCs. miR‐29a and miR‐92a activated the proliferation and function of MDSCs by targeting high‐mobility group box transcription factor 1 (Hbp1) and protein kinase cAMP‐dependent type I regulatory subunit alpha (Prkar1a), respectively. Altogether, the results of our study provide new insights into the role of glioma exosomal miRNAs in mediating the formation of immunosuppressive microenvironments in tumors and elucidate the underlying exosomal miR‐29a/miR‐92a‐based regulatory mechanism responsible for the modulation of functional MDSC induction.

The role of cancer-derived microRNAs in cancer immune escape

“…Ren et al reported that gastric cancer cells enhanced the expansion and activity of MDSCs by delivering miRNA-107enriched exosomes [133]. Similarly, in the condition of hypoxia, glioma secreted exosomal miR-29a and miR-92a which enhanced the proliferation and function of MDSCs via targeting Hbp1 as well as Prkar1a [136]. Besides, this hypoxia-induced glioma could generate exosomal miR-10a and miR-21 to propel the expansion and activation of MDSCs [135].…”

“…Immunosuppressive [125] miR-24-3p NPC Immunosuppressive [126] miR-891a NPC Immunosuppressive [126] miR-106a-5p NPC Immunosuppressive [126] miR-20a-5p NPC Immunosuppressive [126] miR-1908 NPC Immunosuppressive [126] TAMs miR-222-3p EOC Immunosuppressive [127] miR-940 EOC Immunosuppressive [128] miR-21-3p EOC Immunosuppressive [129] miR-125b-5p EOC Immunosuppressive [129] miR-181d-5p EOC Immunosuppressive [129] miR-21 Head and neck cancer Immunosuppressive [130] miR-1246 Colon cancer Immunosuppressive [131] miR-16 Breast cancer Immunostimulatory [132] MDSCs miR-107 Gastric cancer Immunosuppressive [133] miR-21 OSCC Immunosuppressive [134] miR-21 Glioma Immunosuppressive [135] miR-10a Glioma Immunosuppressive [135] miR-29a Glioma Immunosuppressive [136] miR-92a Glioma Immunosuppressive [136] miR-155 CLL Immunosuppressive [137] CAFs miR-27a Gastric cancer Immunosuppressive [138] miR-1247-3p HCC Immunosuppressive [139] miR-21 HCC Immunosuppressive [140] NPC nasopharyngeal carcinoma, TAM tumor-associated macrophage, EOC epithelial ovarian cancer, MDSC myeloid-derived suppressor cell, OSCC oral squamous cell carcinoma, CLL chronic lymphocytic leukemia, CAF cancer-associated fibroblast, HCC hepatocellular carcinoma M2-like phenotype and suppressing the expression of M1 phenotype-associated markers [130]. Similarly, Cooks et al observed that cancer cells harboring TP53 mutation could reprogram neighboring TAMs into pro-tumor state via secreting miR-1246-enriched exosomes [131].…”

Extracellular Vesicles and Tumor-Immune Escape: Biological Functions and Clinical Perspectives

“…This effect was correlated to the increased amount of EVassociated miR-10a and miR-21 that was able to activate MDSCs functions by targeting RAR-related orphan receptor alpha (RORA) and PTEN [30]. Further, the same group identified also TEV-associated miR-29a and miR-92a as responsible for MDSCs increased proliferation, but only miR-92a as the mediator of immunosuppressive functions [31].Further, data published in a very recent study, show that MDSCs, induced by glioblastoma-EVs, inhibit T cell proliferation [32].…”

“…Further, the in vivo injection of miR-107 to mice promoted the accumulation of MDSC in the peripheral blood [28]. The MDSC-mediated immunosuppressive environment was largely described also in glioma [29]; recently, glioma-EVs were described as responsible for this event [30,31]. In a first study, authors showed that glioma EVs collected in hypoxia conditions had an increased ability to activate MDSCs compared to those collected in normoxia.…”

The cancer exosomes: Clinical implications, applications and challenges

“…Myeloid-derived suppressor cell (MDSC) plays a crucial part in regulating the immunosuppressive microenvironment and assisting tumor to escape the immune response. Guo et al 56 elucidated that glioma exosomal miR-29a and miR-92a induced differentiation of functional MDSCs by binding high-mobility group box transcription factor 1 (Hbp1) and cAMP-reliant type I regulatory subunit alpha (Prkar1a) respectively to mediate the formation of immunosuppressive microenvironments in tumors (Table 1). Compared to a normoxic condition, hypoxic evolution mediated by exosomes is also of great significance to the tumor immunosuppressive microenvironment which involves MDSC.…”