In vivo manipulation of dendritic cells to induce therapeutic immunity.
Efficient antigen presentation and T-cell priming are essential components of effective antitumor immunity. Dendritic cells are critical to both of these functions but to date no method has been devised that both targets antigen to these cells and activates them, in situ, in a manner that induces systemic immunity. In this study we combined a dendritic cell growth factor, Flt3 ligand, with a dendritic cell activator, immunostimulatory DNA, and a tumor antigen to activate and load dendritic cells in vivo. Initial studies showed that immunostimulatory DNA not only activates dendritic cells but also prolongs their survival in vivo and in vitro. Following treatment of mice with Flt3 ligand, coadministration of immunostimulatory DNA and antigen induced potent antitumor immunity, resulting in both tumor prevention and regression of existing tumors. CD8 cytotoxic T lymphocytes but not CD4 T cells were required for tumor protection. Natural killer cells also contributed to tumor protection. These results show that dendritic cells can be loaded with antigen and activated, in situ, and provide the basis for dendritic cell- targeted clinical strategies.
Merad
Miriam
M
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
Sugie
Tomoharu
T
Engleman
Edgar G
EG
Fong
Lawrence
L
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D005260:Female; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008545:Melanoma / Q000473:pathology / Q000628:therapy; D008565:Membrane Proteins / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009838:Oligodeoxyribonucleotides / Q000276:immunology / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D019496:Cancer Vaccines; D008565:Membrane Proteins; D009838:Oligodeoxyribonucleotides; C084881:flt3 ligand protein