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

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2010
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Lladser, Álvaro
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Intradermal DNA electroporation induces survivin-speciWc CTLs, suppresses angiogenesis and confers protection against mouse melanoma
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Author
  • Lladser, Álvaro;
  • Ljungberg, Karl;
  • Tufvesson, Helena;
  • Tazzari, Marcella;
  • Roos, Anna-Karin;
  • Quest, Andrew F. G.;
  • Kiessling, Rolf;
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.
Patrocinador
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.
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URI: https://repositorio.uchile.cl/handle/2250/128708
DOI: DOI 10.1007/s00262-009-0725-4
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Cancer Immunol Immunother (2010) 59:81–92
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