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

OK-432的抗肿瘤作用机制及口腔癌新治疗策略的开发

• 批准号: 16592005
• 负责人: OKAMOTO Masato
• 金额: $ 2.3万
• 依托单位: The University of Tokushima
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16592005/
• 关键词: Cancer Immunotherapy; OK-432; Lipoteichoic acid-related molecule OK-PSA; Toll-like receptor 4; phagocytosis; dendritic cell; knock-out mouse; gene transfection; マクロファージ

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.

我们已经成功地分离出OK-432的活性成分，一种脂磷壁酸相关分子OK-PSA，并表明OK-PSA通过Toll样受体（TLR）4增强抗癌免疫力。在目前的研究中，我们证明了OK-432诱导IL-12的能力被细胞松弛素B（一种吞噬抑制剂）抑制，在人树突状细胞（DC）和小鼠腹腔巨噬细胞（PM）中，OK-432被DC和PM捕获并溶解，这些是来自OK-432处理的DC的上清液中的OK-PSA，上清液增加了表达TLR 4的细胞中的核因子-κB活性，并且该活性被识别OK-PSA的TS-2抗体中和，并且OK-432给药导致抑制荷瘤小鼠中的肿瘤生长，并且在来自小鼠的血清中检测到OK-PSA。提示吞噬细胞对OK-432的捕获和TLR 4信号转导在OK-432的抗癌免疫效应中起重要作用。接下来，我们研究了治疗不表达TLR 4的口腔癌患者的策略。DC+OK-432对同基因型荷瘤小鼠无抗肿瘤作用，但转染TLR 4基因后，DC+OK-432对荷瘤小鼠有抗肿瘤作用。这强烈表明，使用TLR 4基因转染的DC +OK-432的治疗可能对不表达TLR 4且被认为对基于OK-432的免疫治疗无应答的癌症患者有效。

项目成果

特集[樹状細胞ワクチン]OK-432を併用した口腔癌に対する樹状細胞療法

专刊【树突状细胞疫苗】使用OK-432治疗口腔癌的树突状细胞疗法

• 发表时间: 2006
• 期刊: BIO Clinica 20・2
• 作者: 岡本正人

Inovolvement of nitric oxide in anti-tumor effects of OK-432, a streptococcal anti-tumor immunotherapeutic agent

一氧化氮参与链球菌抗肿瘤免疫治疗剂 OK-432 的抗肿瘤作用

• 发表时间: 2006
• 期刊: Int Immunopharmacol (in press)(in press)
• 作者: Tatsuro Tanaka;Yasuhiro Morimoto;Shunji Shiiba;Eiji Sakamoto;Shinji Kito;Yuka Matsufuji;Osamu Nakanishi;Takeshi Ohba;Tetsuya Oshikawa
• 通讯作者: Tetsuya Oshikawa

Dendritic cell-therapy in combination with OK-432 in oral cancer.

树突状细胞疗法与 OK-432 联合治疗口腔癌。

• 发表时间: 2006
• 期刊: BIO Clinica 20(2)
• 作者: Eiji Sakamoto;Shiiba Shunji;Kazumi Sakamoto;Osamu Nakanishi et al.;Masato Okamoto
• 通讯作者: Masato Okamoto

Toll-like receptor 4 mediates anti-tumor host response induce by fifty-five kDa protein isolated from Aeginetia indica La parasitic plant

Toll样受体4介导从Aeginetia indica La寄生植物中分离的55 kDa蛋白诱导的抗肿瘤宿主反应

• 发表时间: 2004
• 期刊: Clin Diagn Lab Immun 11・3
• 作者: Hatori M;Nagumo M;Masato Okamoto
• 通讯作者: Masato Okamoto

TLR4欠損マウスにおけるTLR4発現樹状細胞およびOK-432活性成分腫瘍内投与の抗腫瘍効果

表达 TLR4 的树突状细胞的抗肿瘤作用和 OK-432 活性成分对 TLR4 缺陷小鼠的瘤内给药

• 发表时间: 2004
• 期刊: 癌と化学療法 31・11
• 作者: 高田篤史;森本光明;山根源之;高橋愼一他;押川哲也
• 通讯作者: 押川哲也