Expression of toll-like receptor 4 on dendritic cells is significant for anticancer effect of dendritic cell-based immunotherapy in combination with an active component of OK-432, a streptococcal preparation
Expression of toll-like receptor 4 on dendritic cells is significant for anticancer effect of dendritic cell-based immunotherapy in combination with an active component of OK-432, a streptococcal preparation
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DOI：
10.1158/0008-5472.can-03-4005
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发表时间：
2004-08-01
期刊：
影响因子：
11.2
通讯作者：
Sato, M
中科院分区：
文献类型：
--
作者：
Okamoto, M;Furuichi, S;Sato, M
脂磷壁酸相关分子OK-PSA是链球菌衍生的抗癌免疫治疗剂OK-432的活性成分。在本研究中，我们首先观察了OK-PSA对5例健康供者和10例有或不表达Toll样受体4(TLR4)或MD-2mRNA的头颈癌患者的DC体外成熟的影响。经OK-PSA处理后，MHC-II、CD80、CD83、CD86的表面表达明显增加。OK-PSA刺激的DC分泌可诱导辅助性T细胞1型(Th1)型T细胞反应的细胞因子，并刺激同种异体T细胞产生干扰素-γ并诱导同种异体抗原特异性的细胞毒作用。这些活性几乎依赖于TLR4和MD-2基因的表达。接下来，我们研究了同种树突状细胞瘤内给药和OK-PSA对小鼠已建立的肿瘤的体内抗癌作用。选用表达野生型TLR4的C57BL/6小鼠和C57BL/6来源的TLR4基因敲除小鼠(TLR4(-/-))。虽然OK-PSA能促进野生型同基因瘤小鼠DC瘤内注射的抗肿瘤作用，但对TLR4-/-小鼠，OK-PSA及其与DO和OK-PSA联合治疗的抗肿瘤作用不明显。有趣的是，即使在TLR4(-/-)小鼠身上，注射野生型小鼠来源的DC，然后再注射OK-PSA，也显示出显著的抗肿瘤效果。这些发现表明，OK-PSA可能是局部DC治疗的一种有效佐剂，即使在TLR4缺乏的宿主中，当TLR4仅在瘤内注射的DO中表达时，DC治疗之后的OK-PSA也能够诱导出抗癌活性。
A lipoteichoic acid-related molecule OK-PSA is an active component of OK-432, a Streptococcus-derived anticancer immunotherapeutic agent. In the present study, we first examined the effect of OK-PSA on the maturation of dendritic cells (DCs) in vitro by using the DCs derived from 5 healthy donors and 10 patients with head and neck cancer with or without expression of toll-like receptor 4 (TLR4) or MD-2 mRNA. OK-PSA treatment effectively increased the surface expression of MHC class II, CD80, CD83, and CD86. OK-PSA-stimulated DCs secreted the cytokines that can induce helper T-cell 1 (Th1)-type T-cell response, and stimulated allogeneic T cells to produce IFN-gamma and to elicit an allogeneic antigen-specific cytotoxicity. These activities almost depended on expression of TLR4 and MD-2 genes. We next investigated the in vivo anticancer effect of intratumoral administration of syngeneic DCs followed by OK-PSA against established tumors in mice. C57BL/6 mice, which express wild-type TLR4, and C57BL/6-derived TLR4-knockout (TLR4(-/-)) mice were used. Although OK-PSA accelerated the antitumor effect of intratumoral DC administration in wild-type mice bearing syngeneic tumors, the antitumor effect of OK-PSA as well as of the combination therapy with DO and OK-PSA was not significant in TLR4-/- mice. Interestingly, an administration of wild-type-mouse-derived DCs followed by OK-PSA exhibited a marked antitumor effect even in the TLR4(-/-) mice. These findings suggest that OK-PSA may be a potent adjuvant for local DC therapy, and that DC therapy followed by OK-PSA is able to elicit anticancer activity even in a TLR4-deficient host when TLR4 is expressed only in DO injected intratumorally.