Glioblastoma stem cell-derived exosomes induce M2 macrophages and PD-L1 expression on human monocytes

Abstract

Exosomes can mediate a dynamic method of communication between malignancies, including those sequestered in the central nervous system and the immune system. We sought to determine whether exosomes from glioblastoma (GBM)-derived stem cells (GSCs) can induce immunosuppression. We report that GSC-derived exosomes (GDEs) have a predilection for monocytes, the precursor to macrophages. The GDEs traverse the monocyte cytoplasm, cause a reorganization of the actin cytoskeleton, and skew monocytes toward the immune suppresive M2 phenotype, including programmed death-ligand 1 (PD-L1) expression. Mass spectrometry analysis demonstrated that the GDEs contain a variety of components, including members of the signal transducer and activator of transcription 3 (STAT3) pathway that functionally mediate this immune suppressive switch. Western blot analysis revealed that upregulation of PD-L1 in GSC exosome-treated monocytes and GBM-patient-infiltrating CD14+ cells predominantly correlates with increased phosphorylation of STAT3, and in some cases, with phosphorylated p70S6 kinase and Erk1/2. Cumulatively, these data indicate that GDEs are secreted GBM-released factors that are potent modulators of the GBM-associated immunosuppressive microenvironment.

Glioblastoma-Derived IL6 Induces Immunosuppressive Peripheral Myeloid Cell PD-L1 and Promotes Tumor Growth

“…Mechanistically, we determined that GCM-driven PD-L1 induction is STAT3-dependent, with IL6 acting as the primary STAT3 activator. STAT3 directly binds to the PD-L1 promoter (73) and has been implicated in myeloid anti-inflammatory effects (74)(75)(76), such as upregulation of immunosuppressive cytokines (73,77) and GBM exosome induction of myeloid PD-L1 (78). The induction of myeloid B7-H4 was similarly shown to be IL6/STAT3 dependent (32), supporting the notion that IL6 can activate redundant immunosuppressive mechanisms (79).…”

Immunoregulatory Effects of Stem Cell-Derived Extracellular Vesicles on Immune Cells

“…For example, activated CD8+ T cellderived EVs were observed to prevent tumor progression by EV-mediated depletion of mesenchymal stromal/stem cells (MSCs) associated with tumor expansion in tumor environment (33). Glioblastoma SCs (GSCs)-derived EVs induced inclination of human monocytes toward the immunosuppressive M2 phenotype expressing programmed death ligand-1 (PD-L1), leading to the spread of tumor cells (34). Overall, the bidirectional interaction of EVs secreted by SCs and by immune cells has provided a theoretical basis for exploring tissue/organ repair and antitumor mechanisms.…”

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

“…As it is well known, tumor cells overexpress co-inhibitory receptor PD-L1 that binds the inhibitory molecule PD-1 on the activated T cells, driving to their inhibition [60,61]. Interestingly, accumulating evidence report that PD-L1 is contained and delivered by sEVs released many tumor types [62][63][64][65][66][67]; moreover, other studies revealed that TEVs can increase PD-L1 expression on monocytes [68,69]. The correlation between TEVs and PD-1/PD-L1 axis will be extensively discussed in paragraph 3.…”