Glioma Exosomes Mediate the Expansion and Function of Myeloid-derived Suppressor Cells Through MicroRNA-29a/Hbp1 and MicroRNA-92a/Prkar1a Pathways

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.