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

J Gene Med. 2012 Feb;14(2):128-37. doi: 10.1002/jgm.1651.

Abstract

Background: DNA vaccination is an attractive approach for tumor vaccination because plasmid DNA (pDNA) can be used as a 'general vaccine' across major histocompatibility complex 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 that is expressed on dendritic cells (DCs) and T cells. In vivo, CCL19 is a key regulator for the interactions between DCs and T cells in regional lymph nodes.

Methods: 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. Forty-seven days after the tumor challenge, 58% of the mice coinjected with pDNA(Her2/neu) and pDNA(CCL19) remained tumor-free compared to 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 granulocyte macrophage-colony-stimulating factor (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.

MeSH terms

  • Animals
  • Chemokine CCL19 / immunology
  • Chemokine CCL19 / metabolism*
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Enzyme-Linked Immunospot Assay
  • Female
  • Mice
  • Mice, Inbred BALB C
  • Neoplasms / prevention & control*
  • Plasmids / genetics*
  • Receptor, ErbB-2 / genetics*
  • Receptors, CCR7 / immunology
  • Receptors, CCR7 / metabolism*
  • Th1 Cells / immunology
  • Th1 Cells / metabolism
  • Vaccination
  • Vaccines, DNA / genetics*
  • Vaccines, DNA / immunology

Substances

  • Ccr7 protein, mouse
  • Chemokine CCL19
  • Receptors, CCR7
  • Vaccines, DNA
  • Erbb2 protein, mouse
  • Receptor, ErbB-2