Mechanism for anti-tumor effect of OK-432 and development of novel treatment strategy in oral cancer

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We have succeeded in isolating an active component of OK-432, a lipoteichoic acid-related molecule OK-PSA, and have shown that the OK-PSA augments anti-cancer immunity via Toll-like receptor (TLR) 4. In the current study, we demonstrated that IL-12-inducing ability of OK-432 was inhibited by cytochalasin B, a phagocytosis inhibitor, in human dendritic cells (DCs) and in mouse peritoneal macrophages (PMs), that OK-432 was captured and dissolved by DCs and PMs, that these is an OK-PSA in the supernatant derived from OK-432-treated DCs, that the supernatant increased nuclear factor-κB activity in TLR4-expressing cells and the activity was neutralized by TS-2 antibody recognizing OK-PSA, and that OK-432 administration resulted in inhibiting tumor growth in tumor-bearing mice and OK-PSA was detected in the sera from the mice. It was indicated that capture of OK-432 by phagocytes and TLR4 signaling play significant roles in anti-cancer immune effect of OK-432. Next, we investigated the strategy for treating oral cancer patients who do not express TLR4. In syngeneic tumor-bearing TLR4-/- mice, DC+OK-432 therapy did not elicit antitumor effect, however, this therapy was effective when TLR4 gene was transfected into TLR4-/- mice-derived DCs. It was strongly suggested that the therapy using TLR4 gene-transfected DCs+OK-432 may be effectve for the treatment of cancer patients who did not express TLR4 and was supposed non-responder to OK-432-based immunotherapy.