Expression of Toll-like receptor 4 and MD-2 genes in head and neck cancer patients. Molecular targets for cancer immunotherapy with OK-432, a streptococcal agent.

DOI 1 Citations 40 References
  • OKAMOTO Masato
    Second Department of Oral and Maxillofacial Surgery, Tokushima University School of Dentistry
  • TANO Tomoyuki
    Second Department of Oral and Maxillofacial Surgery, Tokushima University School of Dentistry
  • OHE Go
    Second Department of Oral and Maxillofacial Surgery, Tokushima University School of Dentistry
  • FURUICHI Sachiko
    Second Department of Oral and Maxillofacial Surgery, Tokushima University School of Dentistry
  • NISHIKAWA Hidetomo
    Second Department of Oral and Maxillofacial Surgery, Tokushima University School of Dentistry
  • YOSHIDA Hideo
    Second Department of Oral and Maxillofacial Surgery, Tokushima University School of Dentistry
  • SATO Mitsunobu
    Second Department of Oral and Maxillofacial Surgery, Tokushima University School of Dentistry

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Other Title
  • 頭頚部癌患者におけるＴｏｌｌ‐ｌｉｋｅ　ｒｅｃｅｐｔｏｒ４およびＭＤ‐２遺伝子発現　　癌免疫療法剤ＯＫ‐４３２の分子標的
  • Molecular targets for cancer immunotherapy with OK-432, a streptococcal agent
  • 癌免疫療法剤OK-432の分子標的

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There are few reports describing the molecular mechanism of the anti-cancer effect of OK-432, a streptococcal agent. A useful methodology for discrimination between responding and nonresponding patients to OK-432-based immunotherapy has not been established. Toll-like receptors (TLRs) and their cofactors: MD-2 and CD14, are significant receptors to recognize becterial components. In the current study, we examined whether expression of mRNAs for TLRs and cofactors may be associated with responsiveness to OK-432 in head and neck cancer patients. IFN-γ was analyzed as an index of OK-432 responsiveness. The treatment of peripheral blood mononuclear cells (PBMC), derived from the patients in vitro, with OK-432 resulted in an increased expression of IFN-γ mRNA, irrespective of expression of genes for TLR2, TLR4, TLR9, MD-2, and CD14. When PBMC were stimulated in vitro with OK-PSA: a certain effective molecule of OK-432 prepared in our laboratory, the increase of IFN-γ mRNA expression was almost dependent on expression of TLR4 and MD-2. In contrast, amounts of IFN-γ in sera from the patients administered OK-432 were greatly correlated with expression of TLR4 and MD-2. MD-2 is physically associated with TLR4 on the cell surface and plays an essential role for TLR4 signaling. Activation of immune cells by OK-432, irrespective of TLR4/MD-2 signaling, may be insufficient to induce IFN-γ in vivo but not in vitro. These findings strongly suggest that TLR4 and MD-2 may be certain molecular targets for OK-432 therapy, and that expression of these genes may be a useful marker to discriminate between responders and nonresponders to OK-432.

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