Intramuscular immunization with plasmid coexpressing tumour antigen and Flt-3L results in potent tumour regression.
Dendritic cells (DC) are professional antigen-presenting cells capable of initiating a potent primary immune response, making them an attractive target for cancer immunotherapy. Flt-3 ligand (Flt-3L) is a haematopoietic growth factor that efficiently induces DC expansion in vivo. To achieve a more efficient and effective method of priming tumour-specific, DC-mediated immune response, we generated a DNA vaccine comprising both human Flt-3L and the tumour antigen, MUC-1 (pNGVL-hFLex-MUC-1). We report that pNGVL-hFLex-MUC-1 is able to induce antigen-specific CTL immunity in vivo, resulting in a potent anti-tumour response, and that the Flt-3L component is essential to the efficacy of the DNA vaccine. Moreover, the route of immunization is critical in determining the type of immune response generated; intramuscular (i.m.) immunization with pNGVL-hFLex-MUC-1 conferred tumour protection in contrast to poor response with hydrodynamic-based intravenous delivery. Post-i.m. immunization, we observed a massive infiltration of mononuclear cells to the injection site, comprised predominantly of CD11c(+)/CD8alpha(-) DC. Therefore, we propose that Flt-3L acts as an adjuvant to recruit DC, thereby priming the anti-tumour response. However, systemic expansion of DC prior to immunization did not enhance the specific cellular response, suggesting that it is in situ recruitment or expansion of DC that is critical for pNGVL-hFLex-MUC-1 potency.
Fong
C L
CL
Division of Cellular and Molecular Research, National Cancer Centre, Singapore.
Mok
C-L
CL
Hui
K M
KM
D000818:Animals; D017951:Antigen Presentation; D000951:Antigens, Neoplasm; D039521:CD11c Antigen / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D018396:Mucin-1; D009077:Mucins / Q000235:genetics*; D009369:Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D010957:Plasmids; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019444:Vaccines, DNA / Q000008:administration & dosage
D000951:Antigens, Neoplasm; D039521:CD11c Antigen; D016827:CD8 Antigens; C431698:CD8alpha antigen; D019496:Cancer Vaccines; C060192:MUC1 protein, human; D008565:Membrane Proteins; D018396:Mucin-1; D009077:Mucins; D019444:Vaccines, DNA; C084881:flt3 ligand protein