CCL19 (ELC) improves TH1-polarized immune responses and protective immunity in a murine Her2/neu DNA vaccination model.
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.
Department of Hematology, Oncology and Tumor Immunology, Charité-, University Medicine Berlin, Campus Berlin-Buch and Campus Virchow-Klinikum, Germany.
Tam
T
Nguyen-Hoai
Gerd
G
Baldenhofer
Mona Sayed
MS
Ahmed
Minh
M
Pham-Duc
Margarete
M
Gries
Martin
M
Lipp
Bernd
B
Dörken
Antonio
A
Pezzutto
Jörg
J
Westermann
D000818:Animals; D054415:Chemokine CCL19 / Q000276:immunology / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D058501:Enzyme-Linked Immunospot Assay; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000517:prevention & control*; D010957:Plasmids / Q000235:genetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D054400:Receptors, CCR7 / Q000276:immunology / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D014611:Vaccination; D019444:Vaccines, DNA / Q000235:genetics* / Q000276:immunology
D054415:Chemokine CCL19; D018719:Erb-b2 Receptor Tyrosine Kinases; D054400:Receptors, CCR7; D019444:Vaccines, DNA; C515371:Ccr7 protein, mouse; C524056:Erbb2 protein, mouse