Synergistic Induction of Adaptive Antitumor Immunity by Codelivery of Antigen with α-Galactosylceramide on Exosomes

Exosomes and the invariant NKT (iNKT) immune cell ligand alpha-galactosylceramide (alpha GC) may offer novel tools for cancer immunotherapy. In this study, we investigated whether exosomes loaded with alpha GC can activate iNKT cells and potentiate a cancer-specific adaptive immune response. alpha GC loaded exosomes readily activated iNKT cells both in vitro and in vivo. Exosomes loaded with alpha GC plus the model antigen ovalbumin (OVA) induced potent NK and gamma delta T-cell innate immune responses, and they also synergistically amplified T-and B-cell responses that were OVA specific. In contrast to soluble alpha GC, which anergizes iNKT cells, we found that alpha GC/OVA-loaded exosomes did not induce iNKT cell anergy but were more potent than soluble alpha GC + OVA in inducing adaptive immune responses. In an OVA-expressing mouse model of melanoma, treatment of tumor-bearing mice with alpha GC/OVA-loaded exosomes decreased tumor growth, increased antigen-specific CD8(+) T-cell tumor infiltration, and increased median survival, relative to control mice immunized with soluble alpha GC + OVA alone. Notably, an additional injection of alpha GC/OVA-loaded exosomes further augmented the treatment effects. Our findings show that exosomes loaded with protein antigen and alpha GC will activate adaptive immunity in the absence of triggering iNKT-cell anergy, supporting their application in the design of a broad variety of cancer immunotherapy trials. (C) 2013 AACR.