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[Cancer Research 63, 4112-4118, July 15, 2003]
© 2003 American Association for Cancer Research

Immunology

Dendritic Cells Stimulated with a Bacterial Product, OK-432, Efficiently Induce Cytotoxic T Lymphocytes Specific to Tumor Rejection Peptide1

Saori Nakahara, Takuya Tsunoda, Toshiyuki Baba, Shinichi Asabe and Hideaki Tahara2

Department of Surgery and Bioengineering, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan [S. N., T. T., T. B., H. T.], and Immunology Division, Jichi Medical School, Tochigi-Ken 329-0498, Japan [S. A.]

Dendritic cells (DCs) are potent antigen-presenting cells, which have recently been applied for cancer immunotherapy using epitope peptides. Accumulating results of the clinical trials of such a strategy suggest that maturity of the applied DCs has a significant impact on the outcome of the vaccination. Here we examined the effects of penicillin-killed Streptococcus pyogenes (OK-432) on DC maturation and functions including induction of CTLs. DCs generated from peripheral blood using granulocyte macrophage colony-stimulating factor and interleukin (IL)-4 showed immunophenotypes consistent with immature DCs (iDCs). These iDCs were further incubated with medium alone, tumor necrosis factor {alpha}, lipopolysaccharide, or OK-432. The immunophenotypical analysis showed DCs stimulated with OK-432 (OK-DCs) possessed significantly higher expression of CD83 compared with unstimulated DCs. Furthermore, OK-DCs showed significantly higher production of IL-12 and IFN-{gamma} compared with DCs with other stimulations. These results indicate that OK-432 stimulates iDCs to have a mature phenotype and to produce a significant amount of T-helper 1-type cytokines. To examine the potency of OK-DCs on the induction of specific CTLs, the tumor rejection peptide derived from carcinoembryonic antigen was used as a model antigen. The HLA-tetramer assay showed that potent CTL was induced with OK-DCs at high frequency. These results indicate that OK-432 efficiently stimulates DCs without interfering with the presentation of pulsed peptide. Furthermore, OK-432 does not activate nuclear factor {kappa}B through Toll-like receptor 2 or Toll-like receptor 4 in the indicator cell system; however, it induces IL-12 production through the ß2 integrin system on DCs. These results strongly suggest that OK-432 could be applied to develop an efficient cancer vaccine using DCs pulsed with tumor rejection peptides.




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Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
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Copyright © 2003 by the American Association for Cancer Research.