title: Exosomes as potent cell-free peptide-based vaccine. I. Dendritic cell-derived exosomes transfer functional MHC class I/peptide complexes to dendritic cells.
abstract: Current immunization protocols in cancer patients involve CTL-defined tumor peptides. Mature dendritic cells (DC) are the most potent APCs for the priming of naive CD8(+) T cells, eventually leading to tumor eradication. Because DC can secrete MHC class I-bearing exosomes, we addressed whether exosomes pulsed with synthetic peptides could subserve the DC function consisting in MHC class I-restricted, peptide-specific CTL priming in vitro and in vivo. The priming of CTL restricted by HLA-A2 molecules and specific for melanoma peptides was performed: 1) using in vitro stimulations of total blood lymphocytes with autologous DC pulsed with GMP-manufactured autologous exosomes in a series of normal volunteers; 2) in HLA-A2 transgenic mice (HHD2) using exosomes harboring functional HLA-A2/Mart1 peptide complexes. In this study, we show that: 1). DC release abundant MHC class I/peptide complexes transferred within exosomes to other naive DC for efficient CD8(+) T cell priming in vitro; 2). exosomes require nature's adjuvants (mature DC) to efficiently promote the differentiation of melanoma-specific effector T lymphocytes producing IFN-gamma (Tc1) effector lymphocytes in HLA-A2 transgenic mice (HHD2). These data imply that exosomes might be a transfer mechanism of functional MHC class I/peptide complexes to DC for efficient CTL activation in vivo.
authors.affiliation: Unité d'Immunologie, ERM0208 Institut National de la Santé et de la Recherche Médicale, Department of Clinical Biology, Institut Gustave Roussy, Villejuif, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: André
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chaput
authors.forename: Nöel E C
authors.initials: NE
authors.lastname: Schartz
authors.forename: Caroline
authors.initials: C
authors.lastname: Flament
authors.forename: Nathalie
authors.initials: N
authors.lastname: Aubert
authors.forename: Jacky
authors.initials: J
authors.lastname: Bernard
authors.forename: François
authors.initials: F
authors.lastname: Lemonnier
authors.forename: Graça
authors.initials: G
authors.lastname: Raposo
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
authors.forename: Di-Hwei
authors.initials: DH
authors.lastname: Hsu
authors.forename: Thomas
authors.initials: T
authors.lastname: Tursz
authors.forename: Sebastian
authors.initials: S
authors.lastname: Amigorena
authors.forename: Eric
authors.initials: E
authors.lastname: Angevin
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000951:Antigens, Neoplasm; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D002474:Cell-Free System / Q000276:immunology; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism* / Q000637:transplantation; D011992:Endosomes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology; D015789:HLA-A2 Antigen / Q000008:administration & dosage / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000008:administration & dosage / Q000276:immunology*; D006801:Humans; D007399:Interphase / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D058965:MART-1 Antigen; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000008:administration & dosage / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D015395:Histocompatibility Antigens Class I; D058965:MART-1 Antigen; C548667:MLANA protein, human; C548668:Mlana protein, mouse; D009363:Neoplasm Proteins; D022223:Vaccines, Subunit