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

Abstract

Abstract Extracellular vesicles (EV) are important mediators of intercellular communication and are potential candidates for cancer immunotherapy. Immune checkpoint blockade, specifically targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis, mitigates T-cell exhaustion, but is only effective in a subset of patients with cancer. 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 anti–PD-L1 therapy in a checkpoint-refractory B16 melanoma model. Injection of dendritic cell–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 anti–PD-L1 potentiated immune responses to ovalbumin- 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 nonresponsive tumor model.