Lymphocytes genetically modified to express tumor antigens target DCs in vivo and induce antitumor immunity.
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.
Russo
Vincenzo
V
Cancer Gene Therapy Unit, Cancer Immunotherapy and Gene Therapy Program, Scientific Institute H. San Raffaele, Milan, Italy.
Cipponi
Arcadi
A
Raccosta
Laura
L
Rainelli
Cristina
C
Fontana
Raffaella
R
Maggioni
Daniela
D
Lunghi
Francesca
F
Mukenge
Sylvain
S
Ciceri
Fabio
F
Bregni
Marco
M
Bordignon
Claudio
C
Traversari
Catia
C
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
D000951:Antigens, Neoplasm; D001324:Autoantigens; D019013:CD40 Antigens; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase