Toll-Like Receptor-Targeting Immunotherapy for Oral Cancer

DOI 参考文献64件
  • Okamoto Masato
    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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It is important to augment the anti-cancer host response in cancer treatment. Recent studies have suggested that the signaling that occurs via the Toll-like receptors (TLRs), which are newly identified receptor molecules recognizing many pathogens, are involved in the induction of anti-cancer immunity. OK-432, a penicillin-killed and lyophilized preparation of Streptococcus pyogenes, is being successfully used as an immunotherapeutic agent in many types of malignancies. However, the molecular mechanisms of OK-432, a whole bacterial preparation, and the active components which make it effective against cancer, remain uncertain. We have succeeded in isolating the active component of OK-432 (lipoteichoic acid-related molecule, OK-PSA) by affinity chromatography of a butanol extract of OK-432 on the CNBr-activated sepharose 4B bound TS-2 monoclonal antibody that neutralizes the interferon (IFN)-γ-inducing activity of OK-432. OK-PSA induced Th1-type cytokines both in human and in mice, and elicited an anti-cancer effect in tumor-bearing mice via TLR4. Furthermore, our clinical study revealed that TLR4 signaling is intimately involved in the anti-cancer effect achieved by OK-432 in patients with oral cancer. We elucidated that OK-432 is first captured and digested by phagocytes, such as dendritic cells and macrophages, and then its active component, OK-PSA, which is released from the phagocytes, stimulates TLR4 signaling. It is strongly suggested that OK-PSA is the molecule most responsible for the anti-cancer effect of OK-432, and that TLR4 may be a definite molecular target for cancer immunotherapy with OK-432/OK-PSA.

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