Exosomal OX40L elicits positive T cell co-stimulation and promotes anti-tumor immunity through engagement of cytotoxic T lymphocytes

Exosomes play a role in immune regulation associated with cancer and other diseases. We generated exosomes that harbor the ligand of the co-stimulatory OX40 pathway, and demonstrated abundant levels of OX40L on the surface of exosomes, without inducing morphological and molecular alterations. Functionally, exosomal OX40L efficiently elicits positive co-stimulation of both human and murine T cells. The systemic administration of exosomal OX40L promotes anti-tumor immunity in an orthotopic melanoma mouse model, and the depletion of T cell subsets revealed that exosomal OX40L acts through CD8+ T cells. Mechanistically, exosomal OX40L enhances the proportion and the levels of cytotoxic markers in tumor-infiltrating CD8+ T lymphocytes. Taken together, using the OX40 pathway as proxy, we provide proof-of-principle evidence that the presence of positive co-stimulatory molecules on exosomes can functionally engage T cells to elicit anti-tumor immunity, paving the way to understand the biology of exosome-mediate T cell signaling and for further developing exosome-based reagents that engage T cell co-stimulation.