Journal
JOURNAL OF IMMUNOLOGY
Volume 198, Issue 12, Pages 4707-4715Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1600731
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Funding
- Ministry of Health, Labour and Welfare
- Ministry of Education, Culture, Sports, Science and Technology of the Japanese government
- Research on Development of New Drugs
- Emerging/Reemerging Infectious Diseases Project of Japan
- Research Program on HIV/AIDS from Japan Agency for Medical Research and Development
- Grants-in-Aid for Scientific Research [16H05256] Funding Source: KAKEN
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DNAvaccines are attractive immunogens for priming humoral and cellular immune responses to the encoded Ag. However, their ability to induce Ag-specific CD8(+) T cell responses requires improvement. Among the strategies for improving DNA vaccine immunogenicity are booster vaccinations, alternate vaccine formulations, electroporation, and genetic adjuvants, but few, such as extracellular vesicles (EVs), target natural Ag delivery systems. By focusing on CD63, a tetraspanin protein expressed on various cellular membranes, including EVs, we examined whether a DNAvaccine encoding an Ag fused to CD63 delivered into EVs would improve vaccine immunogenicity. In vitro transfection with plasmid DNA encoding an OVA Ag fused to CD63 (pCD63-OVA) produced OVA-carrying EVs. Immunizations with the purified OVA-carrying EVs primed naive mice to induce OVA-specific CD4(+) and CD8(+) T cells, whereas immunization with EVs purified from cells transfected with control plasmids encoding OVA protein alone or a calnexin-OVA fusion protein delivered into the endoplasmic reticulum failed to do so. Vaccinating mice with pCD63-OVA induced potent Ag-specific T cell responses, particularly those from CD8(+) T cells. CD63 delivery into EVs led to better CD8(+) T cell responses than calnexin delivery into the endoplasmic reticulum. When we used a mouse tumor implantation model to evaluate pCD63-OVA as a therapeutic vaccine, the EV-delivered DNA vaccination significantly inhibited tumor growth compared with the control DNA vaccinations. These results indicate that EV Ag delivery via DNA vaccination offers a new strategy for eliciting strong CD8(+) T cell responses to the encoded Ag, making it a potentially useful cancer vaccine.
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