title: Lymphocytes genetically modified to express tumor antigens target DCs in vivo and induce antitumor immunity.
abstract: The exploitation of the physiologic processing and presenting machinery of DCs by in vivo loading of tumor-associated antigens may improve the immunogenic potential and clinical efficacy of DC-based cancer vaccines. Here we show that lymphocytes genetically modified to express self/tumor antigens, acting as antigen carriers, efficiently target DCs in vivo in tumor-bearing mice. The infusion of tyrosinase-related protein 2-transduced (TRP-2-transduced) lymphocytes induced the establishment of protective immunity and long-term memory in tumor-bearing mice. Analysis of the mechanism responsible for the induction of such an immune response allowed us to demonstrate that cross-presentation of the antigen mediated by the CD11c(+)CD8alpha(+) DC subset had occurred. Furthermore, we demonstrated in vivo and in vitro that DCs had undergone activation upon phagocytosis of genetically modified lymphocytes, a process mediated by a cell-to-cell contact mechanism independent of CD40 triggering. Targeting and activation of secondary lymphoid organ-resident DCs endowed antigen-specific T cells with full effector functions, which ultimately increased tumor growth control and animal survival in a therapeutic tumor setting. We conclude that the use of transduced lymphocytes represents an efficient method for the in vivo loading of tumor-associated antigens on DCs.
authors: Cancer Gene Therapy Unit, Cancer Immunotherapy and Gene Therapy Program, Scientific Institute H. San Raffaele, Milan, Italy.
authors: Vincenzo
authors: V
authors: Russo
authors: Arcadi
authors: A
authors: Cipponi
authors: Laura
authors: L
authors: Raccosta
authors: Cristina
authors: C
authors: Rainelli
authors: Raffaella
authors: R
authors: Fontana
authors: Daniela
authors: D
authors: Maggioni
authors: Francesca
authors: F
authors: Lunghi
authors: Sylvain
authors: S
authors: Mukenge
authors: Fabio
authors: F
authors: Ciceri
authors: Marco
authors: M
authors: Bregni
authors: Claudio
authors: C
authors: Bordignon
authors: Catia
authors: C
authors: Traversari
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology; D000951:Antigens, Neoplasm / Q000235:genetics*; D001324:Autoantigens / Q000235:genetics*; D019013:CD40 Antigens / Q000276:immunology; D002450:Cell Communication; D045744:Cell Line, Tumor; D002465:Cell Movement; D003713:Dendritic Cells / Q000276:immunology*; D019746:Intramolecular Oxidoreductases / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology*; D010587:Phagocytosis; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation
chemical_list: D000951:Antigens, Neoplasm; D001324:Autoantigens; D019013:CD40 Antigens; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase