title: Targeting tumor antigens to secreted membrane vesicles in vivo induces efficient antitumor immune responses.
abstract: Expression of non-self antigens by tumors can induce activation of T cells in vivo, although this activation can lead to either immunity or tolerance. CD8+ T-cell activation can be direct (if the tumor expresses MHC class I molecules) or indirect (after the capture and cross-presentation of tumor antigens by dendritic cells). The modes of tumor antigen capture by dendritic cells in vivo remain unclear. Here we examine the immunogenicity of the same model antigen secreted by live tumors either in association with membrane vesicles (exosomes) or as a soluble protein. We have artificially addressed the antigen to secreted vesicles by coupling it to the factor VIII-like C1C2 domain of milk fat globule epidermal growth factor-factor VIII (MFG-E8)/lactadherin. We show that murine fibrosarcoma tumor cells that secrete vesicle-bound antigen grow slower than tumors that secrete soluble antigen in immunocompetent, but not in immunodeficient, host mice. This growth difference is due to the induction of a more potent antigen-specific antitumor immune response in vivo by the vesicle-bound than by the soluble antigen. Finally, in vivo secretion of the vesicle-bound antigen either by tumors or by vaccination with naked DNA protects against soluble antigen-secreting tumors. We conclude that the mode of secretion can determine the immunogenicity of tumor antigens and that manipulation of the mode of antigen secretion may be used to optimize antitumor vaccination protocols.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U653, Paris, France.
authors.forename: Ingrid S
authors.initials: IS
authors.lastname: Zeelenberg
authors.forename: Matias
authors.initials: M
authors.lastname: Ostrowski
authors.forename: Sophie
authors.initials: S
authors.lastname: Krumeich
authors.forename: Angélique
authors.initials: A
authors.lastname: Bobrie
authors.forename: Carolina
authors.initials: C
authors.lastname: Jancic
authors.forename: Alexandre
authors.initials: A
authors.lastname: Boissonnas
authors.forename: Alain
authors.initials: A
authors.lastname: Delcayre
authors.forename: Jean-Bernard
authors.initials: JB
authors.lastname: Le Pecq
authors.forename: Béhazine
authors.initials: B
authors.lastname: Combadière
authors.forename: Sebastian
authors.initials: S
authors.lastname: Amigorena
authors.forename: Clotilde
authors.initials: C
authors.lastname: Théry
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D000954:Antigens, Surface / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology; D002642:Chick Embryo; D005354:Fibrosarcoma / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008894:Milk Proteins / Q000276:immunology; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D022142:Secretory Vesicles / Q000276:immunology*; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D019496:Cancer Vaccines; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D019444:Vaccines, DNA; D010047:Ovalbumin