EPSTEIN-BARR VIRUS LMP1 ENHANCES LEVELS OF MICROVESICLE-ASSOCIATED PD-L1

Abstract

Extracellular vesicles (EVs) circulate throughout the body and carry cargo that can be conferred to proximal or distant cells, making them major delivery vehicles for cellular communication. Epstein-Barr virus (EBV) infected cells release EVs that contain viral proteins such as the major viral oncogene, latent membrane protein 1 (LMP1). LMP1 has been shown to regulate the cellular gene expression of programmed cell death protein 1 ligand (PD-L1). PD-L1, a protein that suppresses the immune system by binding to PD-1, (a receptor found on cytotoxic T cells). PD-L1 has been recently found to be packaged into small EVs contributing to immune evasion of lung cancer cells. Recent studies establish that MVs are shed in very large amounts by tumor cells, and that elevated levels of MVs correlate to disease metastasis and cancers being more aggressive. Here, we demonstrate PD-L1 enrichment in MVs released from nasopharyngeal carcinoma cells and an important function of EBV LMP1 in regulating PD-L1 levels in MVs. These PD-L1+ MVs containing LMP1 likely contribute to the immunosuppressive microenvironment found in EBV-associated cancers. ImportanceAccumulating evidence over the past decade supports that viruses utilize EVs and associated pathways to incorporate viral products to evade eliciting an immune response, while concurrently enabling viral spread or persistence within the host. Considering that viral proteins confer very strong antigenic peptides that will be recognized by T cells, the regulation of the PD-1 pathway by the overexpression of MV-associated PD-L1 may be a strong immune evasion tactic utilized by viruses. The discovery that EBV LMP1 increases PD-L1 microvesicle secretion, identifies a new therapeutic target in immune blockade therapy. We expect that our findings will begin to clarify the mechanism of LMP1-mediated enhanced packaging of PD-L1 into MVs and may produce more specific targets to treat EBV-associated cancers. Consequently, identifying whether a disease is of viral origin through predictive MV biomarkers could further allow for more targeted therapies.