title: In vivo delivery of antigens by adenovirus dodecahedron induces cellular and humoral immune responses to elicit antitumor immunity.
abstract: Cancer vaccines based on virus-like particles (VLPs) vectors may offer many advantages over other antigen-delivery systems and represent an alternative to the ex vivo cell therapy approach. In this study, we describe the use of penton-dodecahedron (Pt-Dd) VLPs from human adenovirus type 3 (Ad3) as cancer vaccine vehicle for specific antigens, based on its unique cellular internalization properties. WW domains from the ubiquitin ligase Nedd4 serve as an adapter to bind the antigen to Pt-Dd. By engineering fusion partners of WW with the model antigen ovalbumin (OVA), Pt-Dd can efficiently deliver WW-OVA in vitro and the Pt-Dd/WW complex can be readily internalized by dendritic cells (DCs). Immunization with WW-OVA/Pt-Dd results in 90% protection against B16-OVA melanoma implantation in syngeneic mice. This high level of protection correlates with the development of OVA-specific CD8(+) T cells. Moreover, vaccination with WW-OVA Pt-Dd induces robust humoral responses in mice as shown by the high levels of anti-OVA antibodies (Abs) detected in serum. Importantly, treatment of mice bearing B16-OVA tumors with WW-OVA/Pt-Dd results in complete tumor regression in 100% of cases. Thus, our data supports a dual role of Pt-Dd as antigen-delivery vector and natural adjuvant, able to generate integrated cellular and humoral responses of broad immunogenic complexity to elicit specific antitumor immunity. Antigen delivery by Pt-Dd vector is a promising novel strategy for development of cancer vaccines with important clinical applications.
authors.affiliation: HumProTher Laboratory, TIMC-ThereX, UMR 5525 CNRS-UJF, Université Joseph Fourier, UFR de Médecine, Domaine de la Merci, La Tronche, France.
authors.forename: Ana
authors.initials: A
authors.lastname: Villegas-Mendez
authors.forename: Marina I
authors.initials: MI
authors.lastname: Garin
authors.forename: Estela
authors.initials: E
authors.lastname: Pineda-Molina
authors.forename: Eugenia
authors.initials: E
authors.lastname: Veratti
authors.forename: Juan A
authors.initials: JA
authors.lastname: Bueren
authors.forename: Pascal
authors.initials: P
authors.lastname: Fender
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Lenormand
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology* / Q000627:therapeutic use*; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology*; D056724:Immunity, Humoral / Q000276:immunology*; D007167:Immunotherapy; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D000075702:Nedd4 Ubiquitin Protein Ligases; D010047:Ovalbumin / Q000276:immunology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D019496:Cancer Vaccines; D056827:Endosomal Sorting Complexes Required for Transport; D014764:Viral Proteins; D010047:Ovalbumin; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases