Intradermal DNA electroporation induces survivin-speciWc CTLs, suppresses angiogenesis and confers protection against mouse melanoma

Abstract

Survivin is an intracellular tumor-associated antigen that is broadly expressed in a large variety of tumors and also in tumor associated endothelial cells but mostly absent in diVerentiated tissues. Naked DNA vaccines targeting survivin have been shown to induce T cell as well as humoral immune responses in mice. However, the lack of epitope-speciWc CD8+ T cell detection and modest tumor protection observed highlight the need for further improvements to develop eVective survivin DNA vaccination approaches. Here, the eYcacy of a human survivin DNA vaccine delivered by intradermal electroporation (EP) was tested. The CD8+ T cell epitope surv20–28 restricted to H-2 Db was identiWed based on in-silico epitope prediction algorithms and binding to MHC class I molecules. Intradermal DNA EP of mice with a human survivin encoding plasmid generated CD8+ cytotoxic T lymphocyte (CTL) responses cross-reactive with the mouse epitope surv20–28, as determined by intracellular IFN- staining, suggesting that self-tolerance has been broken. Survivin-speciWc CTLs displayed an activated eVector phenotype as determined by CD44 and CD107 up-regulation. Vaccinated mice displayed speciWc cytotoxic activity against B16 and peptidepulsed RMA-S cells in vitro as well as against surv20–28 peptide-pulsed target cells in vivo. Importantly, intradermal EP with a survivin DNA vaccine suppressed angiogenesis in vivo and elicited protection against highly aggressive syngeneic B16 melanoma tumor challenge. We conclude that intradermal EP is an attractive method for delivering a survivin DNA vaccine that should be explored also in clinical studies.