Immune Escape Mediated by Exosomal PD-L1 in Cancer

Extracellular vesicles (EVs) are now well established as important mediators of intercellular communication. EVs constitute a diverse group of secreted vesicles which function by the delivery of protein and nucleic acid cargoes from donor to recipient cells. In cancer, tumor cell-derived EVs are shown to promote disease progression by facilitating local reprogramming of the tumor microenvironment. EVs also have more distant systemic effects via transport in biofluids, and therefore have great potential as biomarkers for disease detection and monitoring. Recently, the discovery that EVs derived from glioblastoma cells can mediate immunosuppression by activation of immune checkpoint signaling and T cell dysfunction was reported. Mechanistically we showed that this occurs via direct binding of PD-L1 secreted in EVs, to its receptor PD1 expressed on the surface of activated T cells. This previously unidentified mechanism of tumor immunosuppression has been confirmed in subsequent independent studies, which have demonstrated the biologic importance of this mechanism across multiple tumor types. These studies have established a new and significant paradigm in which PD-L1 containing tumor cell-derived EVs cause immune suppression by the direct engagement of PD1 on T cells, decreasing their activation and providing a further barrier to protect tumors from T cell killing.