Effective strategy of dendritic cell-based immunotherapy for advanced tumor-bearing hosts: the critical role of Th1-dominant immunity.
Although dendritic cell (DC)-based cancer-specific immunotherapy is a potent strategy for various types of carcinomas, few clinical studies have yielded optimal antitumor effects. Systemic immunodeficiency is observed in patients with advanced malignant disease. In this study, we explored the ability to induce antitumor immunity of the cultured monocyte-derived DCs from hosts with advanced malignant disease, using a mouse model. We found remarkable dysfunction of DCs from mice with advanced cancer, which exhibited T helper (Th)2-dominant immunity, and subsequent reduced antitumor immune response. On the other hand, we found dramatic restoration of the ability of DCs to induce optimal antitumor immune responses after systemic administration of streptococcal preparation OK-432 to the tumor-bearing mice, which induced Th1-dominant immunity. In therapeutic experiments, intratumoral injections of immature DCs from the OK-432-treated mice, designated OK-DCs, enhanced inhibition of tumor growth compared with injections of immature DCs from mice with advanced malignancies, designated T-DCs (P < 0.05), leading to significant prolongation in overall survival (P < 0.05). In analysis of cell surface antigens, antigen-presenting capability and interleukin 12 production, we showed functional skewing in T-DCs and significant restorations in OK-DCs. More CD8+ tumor-infiltrating lymphocytes were detected in the mice treated with OK-DCs; furthermore, CTL assays showed that intratumoral injection of OK-DCs induced tumor-specific immune response to spleen as great as those of N-DCs. These results suggested that Th1-dominant immunity might play a crucial role in the differentiation of DCs, and OK-432 might be useful for inducing optimal antitumor effects in DC-based immunotherapy in tumor-bearing hosts.
Mashino
Kohjiro
K
Department of Surgery, Medical Institute of Bioregulation, Kyushu University, Beppu 874-0838, Japan.
Sadanaga
Noriaki
N
Tanaka
Fumiaki
F
Ohta
Mitsuhiko
M
Yamaguchi
Hiroshi
H
Mori
Masaki
M
D000818:Animals; D002455:Cell Division; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology*; D004705:Endocytosis; D005260:Female; D007150:Immunohistochemistry; D007155:Immunologic Factors / Q000494:pharmacology; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000628:therapy*; D010641:Phenotype; D010844:Picibanil / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D007155:Immunologic Factors; D010844:Picibanil; D007371:Interferon-gamma