title: The duration of signaling through CD40 directs biological ability of dendritic cells to induce antitumor immunity.
abstract: Although it has been demonstrated that the functions of dendritic cells (DCs), including Ag capture, Ag presentation, and migratory activity, change dynamically with their maturation, the most appropriate conditioning of DCs for anticancer immunotherapy is still unclear. The help signal is one of the most potent stimuli for DC maturation and is provided by the interaction of CD40 expressed on DCs with CD40 ligand on CD4(+) T cells. To elucidate the appropriate conditioning of DCs for anticancer immunotherapy, we examined the biological activity of DCs stimulated with immobilized anti-CD40 Ab. DCs stimulated for 3 h (3h-DCs) still showed an immature phenotype, but exhibited augmented migration toward secondary lymphoid tissues. Subcutaneous injection of 3h-DCs facilitated priming of T cells, which could mediate potent antitumor therapeutic efficacy, in draining lymph nodes and successfully induced protective immunity. In contrast, 24h-DCs showed a mature phenotype with good Ag presentation ability to induce cell killing by adoptively transferred CD8(+) T cells when injected at tumor sites; however, they showed no migratory activity and were unable to induce protective immunity when injected s.c. This is the first report that functionally distinct DCs, either for the priming phase or for the effector phase, could be obtained by conditioning with CD40 stimulation and that the duration of stimulation determines the biological outcome. The usage of DCs conditioned for the priming phase might provide significant advantages in anticancer immunotherapy.
authors.affiliation: Department of Homeostatic Regulation and Development, Division of Respiratory Medicine, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Watanabe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kagamu
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Yoshizawa
authors.forename: Nanae
authors.initials: N
authors.lastname: Fujita
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tanaka
authors.forename: Junta
authors.initials: J
authors.lastname: Tanaka
authors.forename: Fumitake
authors.initials: F
authors.lastname: Gejyo
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000096:biosynthesis; D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D019013:CD40 Antigens / Q000276:immunology / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D005260:Female; D005354:Fibrosarcoma / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D016219:Immunotherapy, Adoptive / Q000379:methods; D015552:Injections, Intralesional; D007279:Injections, Subcutaneous; D007958:Leukocyte Count; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000096:biosynthesis; D015398:Signal Transduction / Q000276:immunology*; D012878:Skin Neoplasms / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000637:transplantation
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens; C515371:Ccr7 protein, mouse; C497965:Cd86 protein, mouse; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D008562:Membrane Glycoproteins; D054400:Receptors, CCR7; D019707:Receptors, Chemokine