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

Abstract

Glioblastoma is an aggressive brain tumor that evades the immune system; this studyasked whether tiny particles released by glioblastoma cells (extracellular vesicles, or EVs)can influence a specific type of immune cell called a γδ T lymphocyte. For that purpose, wefirst characterize EVs from the U251 glioblastoma cell line and test whether they bind to,enter, and activate γδ T cells, and which molecules on EVs drive that effect. We found thatthe isolated EVs were enriched in medium/large sizes, contained tumor markers includingEGFR and the stress ligands MICA/B, and were taken up by γδ T cells. Exposure tothese EVs increased an early activation marker (CD69), raised production of inflammatoryproteins TNF-α and IFN-γ, and enhanced the T cells’ ability to kill tumor cells. BlockingMICA/BonEVsreduced activation. These results suggest U251-derived EVs can stimulateantitumor γδ T-cell responses via MICA/B, offering a potential avenue to boost immunetherapies and improve outcomes for patients