Small Messengers: Glioblastoma-Derived Extracellular Vesicles Modulate γδ T Lymphocytes Through a MIC-Dependent Mechanism

Glioblastoma (GBM) is the most aggressive and common primary brain tumor, with a median survival of less than a year after diagnosis. γδ T lymphocytes are immune cells that can migrate to tumors and induce malignant cells' apoptosis. Our previous in silico studies showed that higher γδ T-cell infiltration in GBM correlates with better patient survival, and in vitro experiments showed that GMB supernatants promote an antitumoral profile in γδ T cells. Extracellular vesicles (EVs) play a critical role in cell communication, particularly in tumor microenvironment modulation. Here, we studied the mechanisms responsible for γδ T lymphocyte activation by GBM-derived EVs, together with the effect of these EVs on γδ T cells from GBM patients. For that, γδ T cells were purified from peripheral blood, and EVs were obtained from U251 cell supernatants by differential centrifugation. After EV characterization, we evaluated the γδ T cell-EV interaction and γδ T-cell modulation by EVs. Results showed that EVs induced an increase in CD69 expression, cytotoxicity, and TNF-α and IFN-γ production in γδ T cells in a MIC-dependent mechanism. These results provide valuable insights for developing targeted immunotherapies in GBM patients.