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* Division of Gastroenterology and Hepatology, Department of Internal Medicine,
Institute of Clinical Medicine and Research,
Department of Oncology, Institute of DNA Medicine, and
Department of Surgery, Jikei University School of Medicine, Tokyo, Japan;
¶ Saitama Cancer Center Research Institute for Clinical Oncology, Saitama, Japan; and
|| Department of Medicine, Boston University School of Medicine, Boston, MA 02118
Dendritic cell (DC)/tumor cell fusion cells (FCs) can induce potent CTL responses. The therapeutic efficacy of a vaccine requires the improved immunogenicity of both DCs and tumor cells. The DCs stimulated with the TLR agonist penicillin-killed Streptococcus pyogenes (OK-432; OK-DCs) showed higher expression levels of MHC class I and II, CD80, CD86, CD83, IL-12, and heat shock proteins (HSPs) than did immature DCs. Moreover, heat-treated autologous tumor cells displayed a characteristic phenotype with increased expression of HSPs, carcinoembryonic Ag (CEA), MUC1, and MHC class I (HLA-A2 and/or A24). In this study, we have created four types of FC preparation by alternating fusion cell partners: 1) immature DCs fused with unheated tumor cells; 2) immature DCs fused with heat-treated tumor cells; 3) OK-DCs fused with unheated tumor cells; and 4) OK-DCs fused with heat-treated tumor cells. Although OK-DCs fused with unheated tumor cells efficiently enhanced CTL induction, OK-DCs fused with heat-treated tumor cells were most active, as demonstrated by: 1) up-regulation of multiple HSPs, MHC class I and II, CEA, CD80, CD86, CD83, and IL-12; 2) activation of CD4+ and CD8+ T cells able to produce IFN- 
at higher levels; 3) efficient induction of CTL activity specific for CEA or MUC1 or both against autologous tumor; and 4) superior abilities to induce CD107+IFN-+CD8+ T cells and CD154+ IFN-+CD4+ T cells. These results strongly suggest that synergism between OK-DCs and heat-treated tumor cells enhances the immunogenicity of FCs and provides a promising means of inducing therapeutic antitumor immunity.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work has been supported by Grants-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, a Grant-in-Aid of the Japan Medical Association, the Takeda Science Foundation, the Pancreas Research Foundation of Japan, the Jikei University Research Fund, the Promotion and Mutual Aid Corporation for Private School of Japan, and the Science Research Promotion Fund.
2 Address correspondence and reprint requests to Dr. Shigeo Koido, Jikei University School of Medicine, 163-1 Kashiwa-shita, Kashiwa, Chiba 277-8564 Japan. E-mail address: shigeo_koido{at}jikei.ac.jp
3 Abbreviations used in this paper: DC, dendritic cell; TAA, tumor-associated Ag; FC, fusion cell; Imm, immature; MFI, mean fluorescence intensity; Imm/HS-FC, Imm-DC fused with heat-treated tumor cell; OK-DC, OK-432-stimulated DC; OK-FC, OK-DC fused with tumor cell; OK/HS-FC, OK-DC fused with heat-treated tumor cell; CEA, carcinoembryonic Ag.
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