title: DNA vaccine encoding endosome-targeted human papillomavirus type 16 E7 protein generates CD4+ T cell-dependent protection.
abstract: Human papillomavirus type 16 is commonly implicated in cervical cancers. The viral genome encodes potential targets like the oncoprotein E7, expressed in transformed cells but thought to represent a poorly immunogenic antigen. We describe in this work a DNA-based vaccination protocol aimed at inducing an efficient anti-E7 immune response in vivo. Plasmids allowing the expression of the E7 protein in distinct cellular compartments were generated and assayed in an in vivo model of tumor growth. Our data demonstrate that mice vaccinated with a plasmid encoding for an E7 protein fused to a domain of the MHC class II-associated invariant chain (IiE7) were protected against tumor challenge. Mice immunized against an ubiquitinated form of E7 (Ub(Ala)E7) failed to control tumor growth. Protection induced by IiE7 was correlated with the development of CD8+ CTL and required the presence of CD4+ cells. In vitro studies confirmed that the IiE7 fusion protein was expressed at high levels in the endosomal compartment of transfected cells, while the natural and the ubiquitin-modified form of E7 were mainly nuclear. The present study suggests that an efficient anti-tumor response can be induced in vivo by DNA constructs encoding for E7 protein forms localizing at the endosomal compartment.
authors.affiliation: Laboratory of Chemical Biology, Institut de Biologie et de Médecine Moléculaires, Université Libre de Bruxelles, Gosselies, Belgium. jbrulet@ulb.ac.be
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Brulet
authors.forename: Frédéric
authors.initials: F
authors.lastname: Maudoux
authors.forename: Séverine
authors.initials: S
authors.lastname: Thomas
authors.forename: Kris
authors.initials: K
authors.lastname: Thielemans
authors.forename: Arsène
authors.initials: A
authors.lastname: Burny
authors.forename: Oberdan
authors.initials: O
authors.lastname: Leo
authors.forename: Françoise
authors.initials: F
authors.lastname: Bex
authors.forename: Sophie
authors.initials: S
authors.lastname: Hallez
mesh_terms: D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology; D011992:Endosomes / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D005822:Genetic Vectors; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D052162:Human papillomavirus 16 / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D018613:Microscopy, Confocal; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050725:Papillomavirus E7 Proteins; D030361:Papillomavirus Infections / Q000150:complications / Q000276:immunology; D053918:Papillomavirus Vaccines / Q000276:immunology*; D010957:Plasmids / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D014162:Transfection; D025801:Ubiquitin / Q000276:immunology / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000517:prevention & control* / Q000821:virology; D019444:Vaccines, DNA / Q000276:immunology*
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D019496:Cancer Vaccines; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D011993:Recombinant Fusion Proteins; D025801:Ubiquitin; D019444:Vaccines, DNA; C045084:invariant chain; C059731:oncogene protein E7, Human papillomavirus type 16