PTEN loss in glioma cell lines leads to increased extracellular vesicle biogenesis and PD-L1 cargo in a PI3K-dependent manner.

Phosphatase and Tensin Homologue (PTEN) is one of the most frequently lost tumor suppressors in cancer and the predominant negative regulator of the PI3K/AKT signaling axis. A growing body of evidence has highlighted the loss of PTEN with immuno-modulatory functions including the upregulation of the programmed death ligand-1 (PD-L1) and the development of an immunosuppressive tumor immune microenvironment (TIME), which is most likely the result of an altered secretome. Given their roles in immunosuppression and tumor growth, this raises the question of how the loss of PTEN impacts the biogenesis and function of extracellular vesicles (EVs). Here we show that the loss of this tumor suppressor in glioma cells is accompanied by an enhanced ability to produce EVs enriched with PD-L1 that is largely dependent on PI3K activity. We further show that EVs derived from glioma cells lacking PTEN have a greater ability to suppress T cell receptor (TCR) signaling in response to IFN-γ. Taken together, these findings provide important new insights into how the loss of PTEN can contribute to immune evasion and highlights a role for PI3K as a novel regulator of EV biogenesis and the cargo they contain.