1. Synergistic induction of antigen-specific CTL by fusions of TLR-stimulated dendritic cells and heat-stressed tumor cells.
- Author
-
Koido S, Hara E, Homma S, Mitsunaga M, Takahara A, Nagasaki E, Kawahara H, Watanabe M, Toyama Y, Yanagisawa S, Kobayashi S, Yanaga K, Fujise K, Gong J, and Tajiri H
- Subjects
- CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, Cell Proliferation, Cells, Cultured, HSP70 Heat-Shock Proteins biosynthesis, Hot Temperature, Humans, Hybrid Cells, Interferon-gamma metabolism, Interleukin-12 biosynthesis, Lymphocyte Activation immunology, Phenotype, T-Lymphocytes, Cytotoxic cytology, Antigens immunology, Dendritic Cells immunology, Dendritic Cells metabolism, Neoplasms immunology, Neoplasms metabolism, T-Lymphocytes, Cytotoxic immunology, Toll-Like Receptors metabolism
- Abstract
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- gamma 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-gamma+ CD8+ T cells and CD154+ IFN-gamma+ 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.
- Published
- 2007
- Full Text
- View/download PDF