Targeting dendritic cells with antigen via dendritic cell-associated promoters

• Published in: Cancer gene therapy Vol. 19; no. 5; pp. 303 - 311
• Main Authors: Moulin, V, Morgan, M E, Eleveld-Trancikova, D, Haanen, J B A G, Wielders, E, Looman, M W G, Janssen, R A J, Figdor, C G, Jansen, B J H, Adema, G J
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2012; Nature Publishing Group
• Subjects: 631/250/2504/133; 631/61/51/201; Animal models; Animals; Antigen (tumor-associated); Antigen Presentation; Antigens; Antigens, Neoplasm - immunology; Antigens, Neoplasm - metabolism; Biomedical and Life Sciences; Biomedicine; CD11c antigen; CD11c Antigen - genetics; CD11c Antigen - immunology; CD4 antigen; CD8 antigen; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - immunology; Cell proliferation; DC-SIGN protein; DC-STAMP protein; Dendritic cells; Dendritic Cells - immunology; Electroporation; Female; Gene Expression; Gene Therapy; Green fluorescent protein; Immune response; Immunotherapy, Adoptive - methods; Lectins, C-Type - genetics; Lectins, C-Type - immunology; Lymphocytes T; Melanoma, Experimental - immunology; Melanoma, Experimental - therapy; Membrane Proteins - genetics; Membrane Proteins - immunology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - immunology; NIH 3T3 Cells; original-article; Ovalbumin; Physiological aspects; Promoter Regions, Genetic; Promoters; Promoters (Genetics); Receptors, Cell Surface - genetics; Receptors, Cell Surface - immunology; T-Lymphocytes - immunology; Transfection; Vaccines; Vaccines, DNA - genetics; Vaccines, DNA - immunology; Netherlands; tattoo; DNA vaccination; DC-specific promoter; dendritic cell
• ISSN: 0929-1903; 1476-5500
• DOI: 10.1038/cgt.2012.2

The induction of tumor-specific immune responses is largely dependent on the ability of dendritic cells (DCs) to present tumor-associated antigens to T lymphocytes. Therefore, we investigated the use of DC-associated promoter-driven genetic vaccines to specifically target DC in vivo . Restricted expression of vaccine-encoding genes in DC should enhance specificity and improves their safety for clinical applications. Hereto, 3–5 kb upstream sequences of the murine genes encoding CD11c, DC-SIGN, DC-STAMP and Langerin were isolated, characterized and subcloned into enhanced green fluorescent protein (EGFP) reporter constructs. Upon electroporation, EGFP was expressed in DC cell lines, but not in other cell lines, confirming DC-restricted promoter activity. When these promoters were cloned into a construct upstream of the gene for ovalbumin (OVA), it appeared that DC-STAMP promoter-driven expression of OVA (pDCSTAMP/OVA) in DC yielded the most efficient OVA-specific CD4+ and CD8+ T-cell responses in vitro. Administration of pDC-STAMP/OVA in vivo , using the tattoo gun vaccination system, evoked specific immune responses as evidenced in a mouse tumor model. Adoptively transferred pDC-STAMP/OVA-transfected DCs induced strong CD8+ T-cell proliferation in vivo. These experiments demonstrate that our DC-directed promoter constructs are potential tools to restrict antigen expression in DC and could be implemented to modulate DC function by the introduction of relevant proteins.