Intradermal DNA electroporation induces survivin-specific CTLs, suppresses angiogenesis and confers protection against mouse melanoma |
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Authors: | Alvaro Lladser Karl Ljungberg Helena Tufvesson Marcella Tazzari Anna-Karin Roos Andrew F G Quest Rolf Kiessling |
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Institution: | (1) Immune and Gene Therapy Laboratory, Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Karolinska Hospital R8:01, 17176 Stockholm, Sweden;(2) Cyto Pulse Sciences, Inc., Karolinska Institutet Science Park, Fogdevreten 2, 17177 Solna, Sweden;(3) Laboratory of Cellular Communication, FONDAP Center for Molecular Studies of the Cell (CEMC), Facultad de Medicina, Universidad de Chile, Independencia 1027, Santiago, Chile |
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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 differentiated 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-specific CD8+ T cell detection
and modest tumor protection observed highlight the need for further improvements to develop effective survivin DNA vaccination
approaches. Here, the efficacy 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 identified 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-γ staining, suggesting that self-tolerance has been broken. Survivin-specific CTLs displayed
an activated effector phenotype as determined by CD44 and CD107 up-regulation. Vaccinated mice displayed specific cytotoxic
activity against B16 and peptide-pulsed 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. |
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