Effective Strategy of Dendritic Cell-based Immunotherapy for Advanced Tumor-bearing Hosts: the Critical Role of Th1-dominant Immunity 1 This work was supported in part by Grants-in-Aid for Scientific Research on Priority Areas of Cancer 12215116, 11671251, and 12218227; Grants-in-Aid for Scientific Research (B) 12557100 and 12470241 and (C) 12213101, 12671232, and 12670166); Grant-in-Aid for Exploratory Research 13877188; and the Ministry of Education, Culture, Sports, Science and Technology of Japan. This was work was also supported by the Uehara Memorial Foundation, the Naito Foundation, the Casio Science Promotion Foundation, the Foundation for Promotion of Cancer Research in Japan, and the Sagawa Foundation for Promotion of Cancer Research. 1

Effective Strategy of Dendritic Cell-based Immunotherapy for Advanced Tumor-bearing Hosts: the Critical Role of Th1-dominant Immunity ¹

Department of Surgery, Medical Institute of Bioregulation, Kyushu University, Beppu 874-0838, Japan

Abstract

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.

Footnotes

↵1 This work was supported in part by Grants-in-Aid for Scientific Research on Priority Areas of Cancer 12215116, 11671251, and 12218227; Grants-in-Aid for Scientific Research (B) 12557100 and 12470241 and (C) 12213101, 12671232, and 12670166); Grant-in-Aid for Exploratory Research 13877188; and the Ministry of Education, Culture, Sports, Science and Technology of Japan. This was work was also supported by the Uehara Memorial Foundation, the Naito Foundation, the Casio Science Promotion Foundation, the Foundation for Promotion of Cancer Research in Japan, and the Sagawa Foundation for Promotion of Cancer Research.
↵2 To whom requests for reprints should be addressed, at Department of Surgery, Medical Institute of Bioregulation, Kyushu University, 4546 Tsurumibaru, Beppu 874-0838, Japan. Phone: 81-977-27-1650; Fax: 81-977-27-1651; E-mail: mmori{at}beppu.kyushu-u.ac.jp
↵3 The abbreviations used are: DC, dendritic cell; NK, natural killer; IL, interleukin; Th, T helper; KE, Klinishche Einheit; mAb, monoclonal antibody; CM, culture medium; rm, recombinant murine; SEB, Staphylococcal aureus enterotoxin B; mAb, monoclonal antibody; PE, phycoerythrin; MLR, mixed lymphocyte reaction; CD40L, CD40 ligand; MCF, mean channel fluorescence; BrdUrd, 5-bromo-2-dexyuridine; PerCP, Peridinin chlorophyll protein.
- Accepted June 26, 2002.
- Received November 26, 2001.
- Revision received April 29, 2002.
Molecular Cancer Therapeutics