In vivo manipulation of dendritic cells overcomes tolerance to unmodified tumor-associated self antigens and induces potent antitumor immunity.
Most tumor-associated Ags are self proteins that fail to elicit a T cell response as a consequence of immune tolerance. Dendritic cells (DCs) generated ex vivo have been used to break tolerance against such self Ags; however, in vitro manipulation of DCs is cumbersome and difficult to control, resulting in vaccines of variable potency. To address this problem we developed a method for loading and activating DCs, in situ, by first directing sufficient numbers of DCs to peripheral tissues using Flt3 ligand and then delivering a tumor-associated Ag and oligonucleotide containing unmethylated CG motifs to these tissues. In this study, we show in three different tumor models that this method can overcome tolerance and induce effective antitumor immunity. Vaccination resulted in the generation of CD8(+) T and NK cell effectors that mediated durable tumor responses without attacking normal tissues. These findings demonstrate that unmodified tumor-associated self Ags can be targeted to DCs in vivo to induce potent systemic antitumor immunity.
Okano
Fumiyoshi
F
Department of Pathology, Stanford University School of Medicine, Palo Alto, CA 94304, USA.
Merad
Miriam
M
Furumoto
Katsuyoshi
K
Engleman
Edgar G
EG
D000818:Animals; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000276:immunology*; D001324:Autoantigens / Q000008:administration & dosage / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002272:Carcinoembryonic Antigen / Q000008:administration & dosage / Q000276:immunology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005260:Female; D007108:Immune Tolerance; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D008565:Membrane Proteins / Q000008:administration & dosage / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000276:immunology; D010088:Oxidoreductases / Q000008:administration & dosage / Q000276:immunology; D015682:Retroviridae Proteins, Oncogenic / Q000008:administration & dosage / Q000276:immunology; D014759:Viral Envelope Proteins / Q000008:administration & dosage / Q000276:immunology
D000951:Antigens, Neoplasm; D001324:Autoantigens; C408982:CPG-oligonucleotide; D002272:Carcinoembryonic Antigen; D008565:Membrane Proteins; D009838:Oligodeoxyribonucleotides; D015682:Retroviridae Proteins, Oncogenic; D014759:Viral Envelope Proteins; C084881:flt3 ligand protein; D010088:Oxidoreductases; C064056:tyrosinase-related protein-1