Abstract
Exosomes and the invariant NKT (iNKT) immune cell ligand α-galactosylceramide (αGC) may offer novel tools for cancer immunotherapy. In this study, we investigated whether exosomes loaded with αGC can activate iNKT cells and potentiate a cancer-specific adaptive immune response. αGC loaded exosomes readily activated iNKT cells both in vitro and in vivo. Exosomes loaded with αGC plus the model antigen ovalbumin (OVA) induced potent NK and γδ T-cell innate immune responses, and they also synergistically amplified T- and B-cell responses that were OVA specific. In contrast to soluble αGC, which anergizes iNKT cells, we found that αGC/OVA-loaded exosomes did not induce iNKT cell anergy but were more potent than soluble αGC + OVA in inducing adaptive immune responses. In an OVA-expressing mouse model of melanoma, treatment of tumor-bearing mice with αGC/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 αGC + OVA alone. Notably, an additional injection of αGC/OVA-loaded exosomes further augmented the treatment effects. Our findings show that exosomes loaded with protein antigen and αGC 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.
Highlights
Effective antitumor immunity needs activation of both the innate and adaptive immune system to overcome the immune evasion strategies used by tumors
We report that exosomes loaded with aGC and ovalbumin (OVA) activate invariant NKT (iNKT) cells, overcome anergy induction, and amplify tumor-specific adaptive immune responses with implications for the development of novel cancer immunotherapy
We investigated whether exosomes loaded with aGC could activate iNKT cells in vitro
Summary
Effective antitumor immunity needs activation of both the innate and adaptive immune system to overcome the immune evasion strategies used by tumors. We have recently shown that exosomes induce CD4þ and CD8þ T-cell responses in a B cell–dependent manner in vivo [13, 14] where protein loading, but not peptide loading of exosomes enhanced their immunogenicity. We asked whether dendritic cell–derived exosomes, carrying the lipid antigen–presenting molecule CD1d [15, 16], can be loaded with glycolipid antigen to activate invariant NKT (iNKT) cells, a T-cell subset that has been shown to be important for anticancer responses [17] and whether this would boost T- and B-cell responses to a protein antigen on the same exosome. We report that exosomes loaded with aGC and ovalbumin (OVA) activate iNKT cells, overcome anergy induction, and amplify tumor-specific adaptive immune responses with implications for the development of novel cancer immunotherapy
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