Antigen-Loaded Extracellular Vesicles Induce Responsiveness to Anti-PD-1 and Anti-PD-L1 Treatment in a Checkpoint Refractory Melanoma Model.

Extracellular vesicles (EVs) are important mediators of intercellular communication and are potential candidates for cancer immunotherapy. Immune checkpoint blockade, specifically of the PD-1/PD-L1 axis, mitigates T cell exhaustion, but is only effective in a subset of cancer patients. Reasons for therapy resistance include low primary T-cell activation to cancer antigens, poor antigen presentation, and reduced T-cell infiltration into the tumor. Therefore, combination strategies have been extensively explored. Here, we investigated whether EV therapy could induce susceptibility to anti-PD-1 or -PD-L1 therapy in a checkpoint-refractory B16 melanoma model. Injection of dendritic cell (DC)-derived EVs, but not checkpoint blockade induced a potent antigen-specific T cell response and reduced tumor growth in tumor-bearing mice. Combination therapy of EVs and anti-PD-1 or -PD-L1 potentiated immune responses to OVA- and α-galactosylceramide-loaded EVs in the therapeutic model. Moreover, combination therapy resulted in increased survival in a prophylactic tumor model. This demonstrates that EVs can induce potent antitumor immune responses in checkpoint refractory cancer and induce anti-PD-1 or anti-PD-L1 responses in a previously non-responsive tumor model.