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Lipid-Orchestrated Acceleration of Epstein-Barr Virus-Induced B-Cell Lymphoma Via the Secreted Phospholipase A 2-Mediated Modification of Exosomes

Exosomes act as intercellular communicators by transferring protein and microRNA cargoes, yet the role of exosome lipids remains unclear. Here, we show that the pro-tumorigenic action of lymphoma-derived exosomes is augmented via secreted phospholipase A2(sPLA2)-driven lipid metabolism. Hydrolysis of exosomal phospholipids by group X sPLA2, which was induced in macrophages of Epstein-Barr virus (EBV) lymphoma, increased the production of fatty acids, lysophospholipids and their metabolites. sPLA2-treated exosomes were smaller, self-aggregated, showed better uptake, and increased cytokine expression and lipid mediator signaling in tumor associated macrophages. Pharmacological inhibition of endogenous sPLA2 suppressed lymphoma growth in EBV-infected humanized mice; treatment with sPLA2-modified exosomes reversed this phenotype. Further, sPLA2 expression in human large B-cell lymphomas inversely correlated with patient survival. Overall, the sPLA2-mediated exosome modification promotes tumor development.