Abstract
We recently described the induction of an efficient CD8+ T cell-mediated immune response against a tumor-associated antigen (TAA) uploaded in engineered exosomes used as an immunogen delivery tool. This immune response cleared tumor cells inoculated after immunization, and controlled the growth of tumors implanted before immunization. We looked for new protocols aimed at increasing the CD8+ T cell specific response to the antigen uploaded in engineered exosomes, assuming that an optimized CD8+ T cell immune response would correlate with a more effective depletion of tumor cells in the therapeutic setting. By considering HPV-E6 as a model of TAA, we found that the in vitro co-administration of engineered exosomes and ISCOMATRIXTM adjuvant, i.e., an adjuvant composed of purified ISCOPREPTM saponin, cholesterol, and phospholipids, led to a stronger antigen cross-presentation in both B- lymphoblastoid cell lines ( and monocyte-derived immature dendritic cells compared with that induced by the exosomes alone. Consistently, the co-inoculation in mice of ISCOMATRIXTM adjuvant and engineered exosomes induced a significant increase of TAA-specific CD8+ T cells compared to mice immunized with the exosomes alone. This result holds promise for effective usage of exosomes as well as alternative nanovesicles in anti-tumor therapeutic approaches.
Highlights
Exosomes are vesicles of 50–100 nanometers released by basically all cell types
Attempting to improve the potency of the antigen-specific Cytotoxic T Lymphocyte (CTL) response that we previously observed in mice inoculated with Nefmut -based exosomes, we looked for adjuvants already proven to increase the CD8+ T lymphocyte response, and whose molecular composition was expected to not impact the exosome structure
A total of 1 mU of these exosomes were bound to the beads, and incubated with either 5.75, 11.5, or 23 ISCOTM U/mL of ISCOMATRIXTM adjuvant for 1 to 3 h
Summary
Exosomes are vesicles of 50–100 nanometers released by basically all cell types. They are part of the intercellular communication network [1], and are generated by invagination of endosome membranes leading to the formation of intraluminal vesicles which become part of multivesicular bodies [2].They can traffic to the plasma membrane, thereby releasing their vesicular contents upon membrane fusion. Despite the good tolerance of exosomes as cell-free vaccines, their therapeutic efficacy appeared quite limited, posing the need of new methods to increase their immunogenicity. Attempts to address this issue have been performed by engineering desired antigens to increase their association with the external side of exosome membranes [8,9]
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