PhD student Albert Einstein Col. of Med., United States
Introduction/Rationale: Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, characterized by profound immunosuppression that hinders the effect of immunotherapies. Myeloid-derived suppressor cells (MDSCs), which dampen anti-tumor immune responses, are major contributors to this immunosuppression. GBM-derived extracellular vesicles (GBM-EVs) play a critical role in this process by promoting immunosuppressive polarization of myeloid cells. Therefore, targeting EV-myeloid cell interactions represents a novel target to mitigate GBM-mediated immune suppression. However, the precise mechanisms by which GBM-EVs induce an immunosuppressive effect on myeloid cells remain poorly understood.
Methods: Here, we utilize both in vitro and in vivo assays to determine the immunosuppressive functions of GBM-EVs and the effects of pharmacological inhibitors on disrupting the interaction between GBM-EVs and myeloid cells.
Results: Our data show that GBM-EV treatment significantly increases the monocytic MDSCs (mMDSCs) population in vitro (mean difference = 5.87 ± 1.77, 95% CI [2.17-9.56], p = 0.0017). In vivo, retro-orbital administration of EVs isolated from syngeneic murine glioma cell lines (SB28 and GL261) into C57BL/6 mice resulted in splenic contraction (p= 0.006, p= 0.026, respectively), and a profound increase in splenic mMDSCs (p=0.0031) with SB28. To disrupt EV-myeloid interactions, we utilized two pharmacological agents targeting different mechanisms of EV uptake: methyl-β-cyclodextrin (MβCD) and cytochalasin D (CytoD). Our results showed that both treatments significantly reduced mMDSC frequency (CytoD: p=0.023, MBCD: p=0.0056) as well as the expression of immunosuppressive cytokines, including IL-10 (p=0.045, 0.002) and TGF-β (p=0.0068, 0.05).
Conclusion: These findings demonstrate that disrupting GBM-EV and myeloid cell interaction can rescue tumor-mediated immune suppression, providing a foundation for developing novel therapeutic strategies targeting EV-mediated immune suppression in GBM.
