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

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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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Acknowledgments

Related results have been presented previously in a preliminary form at the AACR Special Conference in Cancer Research “Tumor Immunology: New Perspectives”. December 2–5, 2008, Miami, FL, USA. Research described here has been supported by grants from the Swedish Cancer Society, the Swedish Medical Research Council, the Cancer Society of Stockholm, the European Union (Grants “EUCAAD” and “DC-THERA”), the Karolinska Institutet, “ALF-Project” grants from the Stockholm City Council (to RK), as well as the ICGEB (International Center of Genetic Engineering and Biotechnology, Trieste, Italy) grant CRP/CH102-01, Wellcome Trust award WT06491I/Z/01/Z and FONDAP grant 15010006 (to AFGQ). AL has been supported by President of the Republic International Fellowship for Postgraduate Studies, CONICYT Ph.D. Fellowship award, MECESUP Fellowship awards UCH9903 and UCH0306. KL has been supported by a postdoctoral fellowship from the Swedish Society for Medical Research.

Conflict of interest statement

The authors declare that they have no conflict of interest. AKR is an employee at Cyto Pulse Sciences Inc.

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Authors and Affiliations

  1. Immune and Gene Therapy Laboratory, Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Karolinska Hospital R8:01, 17176, Stockholm, Sweden

    Alvaro Lladser, Karl Ljungberg, Helena Tufvesson, Marcella Tazzari & Rolf Kiessling

  2. Cyto Pulse Sciences, Inc., Karolinska Institutet Science Park, Fogdevreten 2, 17177, Solna, Sweden

    Anna-Karin Roos

  3. Laboratory of Cellular Communication, FONDAP Center for Molecular Studies of the Cell (CEMC), Facultad de Medicina, Universidad de Chile, Independencia 1027, Santiago, Chile

    Andrew F. G. Quest

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  1. Alvaro Lladser
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  2. Karl Ljungberg
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  3. Helena Tufvesson
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  4. Marcella Tazzari
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  5. Anna-Karin Roos
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  7. Rolf Kiessling
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Correspondence to Alvaro Lladser.

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Lladser, A., Ljungberg, K., Tufvesson, H. et al. Intradermal DNA electroporation induces survivin-specific CTLs, suppresses angiogenesis and confers protection against mouse melanoma. Cancer Immunol Immunother 59, 81–92 (2010). https://doi.org/10.1007/s00262-009-0725-4

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  • DOI: https://doi.org/10.1007/s00262-009-0725-4

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