title: Targeted delivery of α-galactosylceramide to CD8α+ dendritic cells optimizes type I NKT cell-based antitumor responses.
abstract: Immunotherapy aiming at enhancing innate and acquired host immunity is a promising approach for cancer treatment. The invariant NKT (iNKT) cell ligand α-galactosylceramide (α-GalCer) holds great promise in cancer therapy, although several concerns limit its use in clinics, including the uncontrolled response it promotes when delivered in a nonvectorized form. Therefore, development of delivery systems to in vivo target immune cells might be a valuable option to optimize iNKT cell-based antitumor responses. Using dendritic cell (DC)-depleted mice, DC transfer experiments, and in vivo active cell targeting, we show that presentation of α-GalCer by DCs not only triggers optimal primary iNKT cell stimulation, but also maintains secondary iNKT cell activation after challenge. Furthermore, targeted delivery of α-GalCer to CD8α(+) DCs, by means of anti-DEC205 decorated nanoparticles, enhances iNKT cell-based transactivation of NK cells, DCs, and γδ T cells. We report that codelivery of α-GalCer and protein Ag to CD8α(+) DCs triggers optimal Ag-specific Ab and cytotoxic CD8(+) T cell responses. Finally, we show that targeting nanoparticles containing α-GalCer and Ag to CD8α(+) DCs promotes potent antitumor responses, both in prophylactic and in therapeutic settings. Our data may have important implications in tumor immunotherapy and vaccine development.
authors.affiliation: Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, F-59019 Lille, France; Université Lille Nord de France, F-59000 Lille, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8204, F-59021 Lille, France; INSERM, U1019, F-59019 Lille, France; Institut Fédératif de Recherche 142, F-59019 Lille, France;
authors.forename: Elodie
authors.initials: E
authors.lastname: Macho-Fernandez
authors.affiliation: Department of Endocrinology, Leiden University Medical Center, 2333 Leiden, The Netherlands; and.
authors.forename: Luis Javier
authors.initials: LJ
authors.lastname: Cruz
authors.affiliation: Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, F-59019 Lille, France; Université Lille Nord de France, F-59000 Lille, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8204, F-59021 Lille, France; INSERM, U1019, F-59019 Lille, France; Institut Fédératif de Recherche 142, F-59019 Lille, France;
authors.forename: Reem
authors.initials: R
authors.lastname: Ghinnagow
authors.affiliation: Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, F-59019 Lille, France; Université Lille Nord de France, F-59000 Lille, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8204, F-59021 Lille, France; INSERM, U1019, F-59019 Lille, France; Institut Fédératif de Recherche 142, F-59019 Lille, France;
authors.forename: Josette
authors.initials: J
authors.lastname: Fontaine
authors.affiliation: Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, F-59019 Lille, France; Université Lille Nord de France, F-59000 Lille, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8204, F-59021 Lille, France; INSERM, U1019, F-59019 Lille, France; Institut Fédératif de Recherche 142, F-59019 Lille, France;
authors.forename: Emilie
authors.initials: E
authors.lastname: Bialecki
authors.affiliation: Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7199, Université de Strasbourg, F-67401 Illkirch Cedex, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Frisch
authors.affiliation: Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, F-59019 Lille, France; Université Lille Nord de France, F-59000 Lille, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8204, F-59021 Lille, France; INSERM, U1019, F-59019 Lille, France; Institut Fédératif de Recherche 142, F-59019 Lille, France; francois.trottein@pasteur-lille.fr.
authors.forename: François
authors.initials: F
authors.lastname: Trottein
authors.affiliation: Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, F-59019 Lille, France; Université Lille Nord de France, F-59000 Lille, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8204, F-59021 Lille, France; INSERM, U1019, F-59019 Lille, France; Institut Fédératif de Recherche 142, F-59019 Lille, France;
authors.forename: Christelle
authors.initials: C
authors.lastname: Faveeuw
mesh_terms: D000818:Animals; D000906:Antibodies / Q000737:chemistry / Q000276:immunology; D017951:Antigen Presentation / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods; D005699:Galactosylceramides / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*; D037181:Lectins, C-Type / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D047368:Tumor Burden / Q000276:immunology
chemical_list: D000906:Antibodies; D015703:Antigens, CD; D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; C093569:DEC-205 receptor; D005699:Galactosylceramides; D037181:Lectins, C-Type; D015778:Minor Histocompatibility Antigens; D016692:Receptors, Antigen, T-Cell, gamma-delta; D011956:Receptors, Cell Surface; C493154:alpha-galactosylceramide