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CCL19 (ELC) improves TH1-polarized immune responses and protective immunity in a murine Her2/neu DNA vaccination model

Authors

  • T. Nguyen-Hoai
  • G. Baldenhofer
  • M.S. Ahmed
  • M. Pham-Duc
  • M. Gries
  • M. Lipp
  • B. Doerken
  • A. Pezzutto
  • J. Westermann

Journal

  • Journal of Gene Medicine

Citation

  • J Gene Med 14 (2): 128-137

Abstract

  • BACKGROUND: DNA vaccination is an attractive approach for tumor vaccination since plasmid DNA can be used as a "general vaccine" across MHC barriers. Coexpression of immunomodulatory molecules can help to amplify the immunogenicity of DNA vaccines. CCL19 (ELC) is a CC chemokine with immunoregulatory properties, binding to the chemokine receptor CCR7 which is expressed on dendritic cells (DC) and T cells. In vivo, CCL19 is a key regulator for the interactions between DC and T cells in regional lymph nodes. METHODS: Plasmid DNA (pDNA) encoding Her2/neu and CCL19 was used as an intramuscular vaccine. Vaccination was performed in BALB/c mice which were subsequently challenged with syngeneic Her2/neu + tumor cells. Groups of mice were immunized with pDNA(Her2/neu) plus pDNA(CCL19), pDNA(Her2/neu) plus pDNA(CCL19) plus pDNA(GM-CSF), pDNA(Her2/neu) plus pDNA(GM-CSF), pDNA(Her2/neu), pDNA(CCL19), pDNA(GM-CSF) or mock vector. Tumor protection by the vaccine and immune responses were monitored. RESULTS: Coadministration of pDNA(Her2/neu) and pDNA(CCL19) led to substantial improvement of tumor protection by the vaccine and induced a TH1-polarized, Her2/neu-specific immune response. 47 days after the tumor challenge, 58% of the mice coinjected with pDNA (Her2/neu) and pDNA(CCL19) remained tumor-free as compared with 22% after vaccination with pDNA(Her2/neu) alone. Additional administration of pDNA(GM-CSF) led to further improvement of tumor protection and an amplification of Her2/neu-specific immune responses. CONCLUSIONS: CCL19 is able to induce a TH-1 polarization of the anti Her2/neu immune response which can be further amplified by GM-CSF. Clinical use of a pDNA(Her2/neu-CCL19 ± GM-CSF) vaccine might be promising in Her2/neu + breast cancer in the clinical situation of minimal residual disease.


DOI

doi:10.1002/jgm.1651