title: Killer dendritic cells link innate and adaptive immunity against established osteosarcoma in rats.
abstract: We have previously reported that a distinct subset of splenic CD4(-) rat dendritic cells (DC) induces a rapid and caspase-independent apoptosis-like cell death in a large number of tumor cells in vitro. The killing activity of these killer DC (KDC) was restricted to their immature state and was immediately followed by their engulfment of the apoptotic target cells, suggesting that these KDC could directly link innate and adaptive immunity to tumors. Here, we addressed this question using a transplantable model of rat osteosarcoma. First, we showed that rat KDC have an MHC II(+)CD103(+)CD11b(+)NKp46(-) phenotype and are therefore distinct from natural killer cells, which are MHC II(-)CD103(-)CD11b(-)NKp46(+). KDC numbers could be specifically and strongly (up to 10-fold) enhanced by Flt3L in vivo. The OSRGa cell line derived from the osteosarcoma tumor was killed and phagocytosed in vitro by both normal and Flt3L-induced splenic KDC. Such tumor antigen-loaded KDC were used to s.c. vaccinate progressive tumor-bearing rats. Vaccination with OSRGa-loaded KDC but not KDC loaded with irrelevant tumor cells (Jurkat) delayed tumor progression or even induced tumor regression. This vaccine effect was not observed in CD8 T cell-depleted animals and protective against tumor rechallenge. These results suggest that KDC possess the intrinsic capability not only to kill and then engulf tumor cells but also to efficiently cross-present tumor cell-derived antigen in vivo and subsequently induce an adaptive antitumor immune response.
authors.affiliation: Institut National de la Sante et de la Recherche Medicale, U643, CHU Nantes, Institut de Transplantation et de Recherche en Transplantation-Urologie-Néphrologie, IUN, Université de Nantes, Faculté de Médecine, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Chauvin
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Philippeau
authors.forename: Caroline
authors.initials: C
authors.lastname: Hémont
authors.forename: Francois-Xavier
authors.initials: FX
authors.lastname: Hubert
authors.forename: Yohann
authors.initials: Y
authors.lastname: Wittrant
authors.forename: Francois
authors.initials: F
authors.lastname: Lamoureux
authors.forename: Benjamin
authors.initials: B
authors.lastname: Trinité
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
authors.forename: Françoise
authors.initials: F
authors.lastname: Rédini
authors.forename: Régis
authors.initials: R
authors.lastname: Josien
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D015703:Antigens, CD / Q000032:analysis*; D001859:Bone Neoplasms / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D003713:Dendritic Cells / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D006801:Humans; D007113:Immunity, Innate; D039001:Integrin alpha Chains / Q000032:analysis*; D019169:Jurkat Cells; D008565:Membrane Proteins / Q000502:physiology; D012516:Osteosarcoma / Q000276:immunology*; D010587:Phagocytosis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014611:Vaccination
chemical_list: D015703:Antigens, CD; D000949:Histocompatibility Antigens Class II; D039001:Integrin alpha Chains; D008565:Membrane Proteins; C091367:alpha E integrins; C084881:flt3 ligand protein