Tumor-derived exosomes deliver the tumor suppressor miR-3591-3p to induce M2 macrophage polarization and promote glioma progression

Abstract

Exosomes can selectively secrete harmful metabolic substances from cells to maintain cellular homeostasis, and complex crosstalk occurs between exosomes and tumor-associated macrophages (TAMs) in the glioma immune microenvironment. However, the precise mechanisms by which these exosome-encapsulated cargos create an immunosuppressive microenvironment remain unclear. Herein, we investigated the effect of glioma-derived exosomes (GDEs) on macrophage polarization and glioma progression. We performed sequencing analysis of cerebrospinal fluid (CSF) and tumor tissues from glioma patients to identify functional microRNAs (miRNAs). High levels of miR-3591-3p were found in CSF and GDEs but not in normal brain tissue or glial cells. Functionally, GDEs and miR-3591-3p significantly induced M2 macrophage polarization and increased the secretion of IL10 and TGFβ1, which in turn promoted glioma invasion and migration. Moreover, miR-3591-3p overexpression in glioma cell lines resulted in G2/M arrest and markedly increased apoptosis. Mechanistically, miR-3591-3p can directly target CBLB and MAPK1 in macrophages and glioma cells, respectively, and further activate the JAK2/PI3K/AKT/mTOR, JAK2/STAT3, and MAPK signaling pathways. In vivo experiments confirmed that macrophages lentivirally transduced with miR-3591-3p can significantly promote glioma progression. Thus, our study demonstrates that tumor-suppressive miR-3591-3p in glioma cells can be secreted via exosomes and target TAMs to induce the formation of an immunosuppressive microenvironment. Collectively, these findings provide new insights into the role of glioma exosomal miRNAs in mediating the establishment of an immunosuppressive tumor microenvironment and show that miR-3591-3p may be a valuable biomarker and that blocking the encapsulation of miR-3591-3p into exosomes may become a novel immunotherapeutic strategy for glioma.

Advances in the role of STAT3 in macrophage polarization

“…Zeng et al also found that activation of the JAK2/ STAT3 signaling pathway promoted the polarization of M2 macrophages, which in turn decreased the levels of inflammatory factors IL-1b, TNF-a and IL-18 while increasing the levels of antiinflammatory factor IL-10 significantly improved the skin lesions in mice with atopic dermatitis (44). Other studies, especially those related to tumor diseases such as ovarian cancer and glioma, have shown that activation of the JAK/STAT3 signaling axis facilitates M2 macrophage polarization and affects disease progression by activating or inhibiting related cytokines (45)(46)(47)(48)(49). The two completely opposite types of results imply that macrophage polarization is not only related to the heterogeneity of STAT3 and macrophages themselves, but also influenced by the JAK/ STAT3 pathway, as well as multiple cytokines, chemokines, immune cells, tumor cells, and crosstalk of different signaling pathways in macrophages (50, 51).…”

CircRNA LOC729852 promotes bladder cancer progression by regulating macrophage polarization and recruitment via the miR‐769‐5p/IL‐10 axis

“…Studies show that TAMs tend to polarize to the M2 phenotype by activating the JAK2/STAT3 pathway. For instance, IL‐8, MAPK, IL‐6, IRF3, IL‐10 and even cigarette extracts can promote M2 polarization in TAMs by activating the JAK2/STAT3 pathway 49–53 . On the other hand, ceramide and palmitic acid are known to inhibit M2 polarization by downregulating IL‐10 88 .…”

Managing the immune microenvironment of osteosarcoma: the outlook for osteosarcoma treatment

“…Osteosarcoma tissue is surrounded by massive immune cell infiltration, resulting in the creation of a complex immune microenvironment that allows osteosarcoma cells to grow within the bone by creating an immunosuppressive microenvironment to maintain their survival and proliferation. [35][36][37] A robust immunosuppressive microenvironment is positively correlated with overactivation of molecules associated with immune suppression, such as indoleamine 2,3-dioxygenase (IDO), programmed cell death protein 1 (PD-1), interleukin-10 (IL-10), transforming growth factor-β (TGF-β), vascular endothelial growth factor (VEGF), and signal transducer and activator of transcription 3 (STAT3), due to their immunosuppressive effects mediated by myeloid-derived suppressor cells (MDSCs), TAMs, and regulatory T lymphocytes (Tregs) [38][39][40][41][42][43] (Fig. 2).…”