title: DNA vaccines employing intracellular targeting strategies and a strategy to prolong dendritic cell life generate a higher number of CD8+ memory T cells and better long-term antitumor effects compared with a DNA prime-vaccinia boost regimen.
abstract: We have previously shown that intradermal coadministration of DNA encoding Bcl-x(L), an antiapoptotic protein, with DNA encoding E7 antigen linked to the sorting signal of the lysosome-associated membrane protein type 1 (Sig/E7/LAMP-1) prolongs dendritic cell life and enhances antigen presentation through the MHC class I and II pathways. In the current study, we compared this approach with a conventional DNA prime-vaccinia boost protocol on the basis of their ability to generate antigen-specific CD8(+) memory T cells and longterm antitumor effects against an E7-expressing tumor. Mice primed and boosted with Sig/E7/LAMP-1 DNA mixed with Bcl-x(L) DNA generated significantly higher numbers of E7-specific CD8(+) memory T cells and a better long-term protective antitumor effect compared with mice primed with Sig/E7/LAMP-1 DNA and boosted with Sig/E7/LAMP-1 vaccinia (Vac-Sig/E7/LAMP-1). Furthermore, coadministration of Sig/E7 /LAMP-1 DNA mixed with Bcl-x(L) DNA also generated higher avidity E7-specific CD8(+) T cells than did vaccination with Sig/E7/LAMP-1 DNA followed by a Vac-Sig/E7/LAMP-1 booster. Our results indicate that coadministration of a DNA vaccine employing intracellular targeting strategies and a DNA encoding antiapoptotic proteins may potentially generate a higher number of memory CD8(+) T cells and better long-term protective antitumor effects compared with the conventional DNA prime-vaccinia boost regimen.
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
authors.forename: Tae Woo
authors.initials: TW
authors.lastname: Kim
authors.forename: Jin-Hyup
authors.initials: JH
authors.lastname: Lee
authors.forename: Liangmei
authors.initials: L
authors.lastname: He
authors.forename: David A K
authors.initials: DA
authors.lastname: Boyd
authors.forename: Chien-Fu
authors.initials: CF
authors.lastname: Hung
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology*; D016503:Drug Delivery Systems; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D018390:Gene Targeting; D007371:Interferon-gamma / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051907:Lysosomal Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D009856:Oncogene Proteins, Viral / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D050725:Papillomavirus E7 Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D018417:Th1 Cells / Q000276:immunology / Q000821:virology; D019444:Vaccines, DNA / Q000008:administration & dosage*; D014616:Vaccinia virus / Q000235:genetics; D051020:bcl-X Protein
chemical_list: D015703:Antigens, CD; C494812:Bcl2l1 protein, mouse; D018984:Epitopes, T-Lymphocyte; D051907:Lysosomal Membrane Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019444:Vaccines, DNA; D051020:bcl-X Protein; C059731:oncogene protein E7, Human papillomavirus type 16; D007371:Interferon-gamma