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An analysis for mechanism of antitumor effects of IL-18 and a clinical application of IL-18 for head and neck tumors

IL-18抗肿瘤作用机制分析及IL-18治疗头颈部肿瘤的临床应用

基本信息

批准号：
12671921
负责人：
ECHIGO Seishi
金额：
$ 2.11万
依托单位：
TOHOKU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671921/
关键词：
IL-18 antitumor effect NK cells IFN-γ IL-12 dendritic cells innate immunity specific immunity CTL

项目摘要

To clarify the antitumor effects of interleukin 18 (IL-18), an effector mechanism of IL-18 was analyzed in murine tumor model. We revealed that NK cells but not NKT cells play a necessary role to promote an innate antitumor response induced by IL-18. Moreover, we hypothesized that antitumor-specific immunity, which is induced by IL-18 treatment in murine tumor models, is promoted by enhancing NK-mediated destruction of tumor and delivery to dendritic cells (DCs). We assesed the effect of IL-18 added to cultures of live tumor cells, NK cells, DCs, and T cells and revealed that IL-18 induces tumor-specific immunity through enhancing NK activity, which in turn mediates tumor cell death and activates and primes DCs.Next, we investigated the in vitro effects of combining IL-18 and IL-2 on human lymphocytes. The combined use of these two cytokines synergistically enhanced IFN-γ production. Phenotypic analysis revealed a preferential expansion of CD56+ CD3- (NK) cells. To reveal that human lymphocytes activated by IL-18 induce tumor apoptosis, tumor cells were stained with Annexin-V, PhiPhiLux, or PI after 8 hours culture with lymphocytes activated by IL-18. Apoptosis of tumor cells were observed on combined use of these cytokines. These results revealed that IL-18 induces antitumor effects in human system. Therefore, the combined use of IL-2 and IL-18 should be considered a voable strategy for the generation of antitumor responses in vivo and for future clinical applications.

为了阐明白细胞介素18（IL-18）的抗肿瘤作用，在小鼠肿瘤模型中分析了IL-18的效应机制。我们发现，NK细胞，而不是NKT细胞发挥必要的作用，以促进先天性抗肿瘤反应诱导的IL-18。此外，我们假设，抗肿瘤特异性免疫，这是由IL-18治疗诱导的小鼠肿瘤模型，是通过增强NK介导的破坏肿瘤和交付树突状细胞（DC）。我们评估了将IL-18添加到活肿瘤细胞、NK细胞、DC和T细胞培养物中的效果，并揭示了IL-18通过增强NK活性诱导肿瘤特异性免疫，这反过来介导肿瘤细胞死亡并激活和引发DCs。这两种细胞因子的组合使用协同增强IFN-γ产生。表型分析显示CD 56 + CD 3-（NK）细胞的优先扩增。为了揭示由IL-18活化的人淋巴细胞诱导肿瘤细胞凋亡，在与由IL-18活化的淋巴细胞一起培养8小时后，用膜联蛋白-V、PhiPhiLux或PI对肿瘤细胞进行染色。联合应用可引起肿瘤细胞凋亡。这些结果表明IL-18在人体系统中诱导抗肿瘤作用。因此，IL-2和IL-18的联合使用应被认为是体内产生抗肿瘤应答和未来临床应用的可行策略。