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Interleukin-18 activates Natural Killer cells and induces tumor apoptosis ; clinical applications for head and neck tumors.

Interleukin-18激活自然杀伤细胞并诱导肿瘤细胞凋亡；

基本信息

批准号：
14370655
负责人：
ECHIGO Seishi
金额：
$ 7.36万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370655/
关键词：
IL-18 antitumor natural killer cells IFN-γ apoptosis dendriticcells innate immunity specific immunity

项目摘要

We have investigated the antitumor effects of IL-18 in marine and human models and reported that IL-18 activated natural killer cells and induced tumor apoptosis. Moreover, tumor apoptosis induced tumor specific cytotoxic T lymphocytes (CTL) by using dendritic cells.We investigated the antitumor effects of combining IL-18 and IL-2 on human peripheral blood mononuclear cells. The combination of these two cytokines produced a large amount of IFN-γ and enhanced tumor cell death against tumor cell lines. Moreover, phenotypic analysis revealed an expansion of CD56+ CD161+ CD3-NK cells on PBMC.In this project, we investigated the antitumor effects of IL-18 in human model in detail. We revealed that co-culture with tumor cells and PBMC activated by IL-2 and IL-18 induced tumor apoptosis on human squamous cell carcinoma cell line. Next, we examined the expression of TRAIL and FasL on IL-18-stimulated PBMC by using RT PCR and revealed that TRAIL and FasL mRNA were upregulated by IL-18 stimulation. These results suggest that TRAIL and FasL play critical role for IL-18-induced tumor apoptosis.Next, we analyzed a response to IL-18 on PBMC from oral cancer patient. We collected patients' PBMC before and after chemotherapy, and investigated changes of NK or T cells. In this study, we have applied to committee of Tohoku University Hospital for the clinical application and were permitted. Then, we have started to collect clinical samples and got some samples. But we cannot analyze data because sample numbers were not so much. We hope that we will continue collecting samples from cancer patients and develop cancer immunotherapy by using IL-18.

我们研究了IL-18在海洋和人类模型中的抗肿瘤作用，并报道了IL-18激活自然杀伤细胞并诱导肿瘤细胞凋亡。此外，肿瘤细胞凋亡诱导肿瘤特异性细胞毒性T淋巴细胞（CTL）的树突状细胞，IL-18和IL-2联合应用对人外周血单个核细胞的抗肿瘤作用。这两种细胞因子的组合产生大量IFN-γ并增强肿瘤细胞对肿瘤细胞系的死亡。此外，表型分析显示，在PBMC上的CD 56 + CD 161 + CD 3-NK细胞的扩增。结果表明，IL-2和IL-18激活的PBMC与肿瘤细胞共培养可诱导人鳞癌细胞凋亡。接下来，我们通过使用RT PCR检测IL-18刺激的PBMC上的TRAIL和FasL的表达，并显示IL-18刺激上调TRAIL和FasL mRNA。这些结果表明TRAIL和FasL在IL-18诱导的肿瘤细胞凋亡中起关键作用。接下来，我们分析了口腔癌患者PBMC对IL-18的反应。分别于化疗前后采集患者外周血单个核细胞（PBMC），观察NK细胞和T细胞的变化。在本研究中，我们向东北大学医院委员会申请了临床应用，并获得了许可。然后，我们已经开始收集临床样本，并获得了一些样本。但是我们不能分析数据，因为样本数量不是那么多。我们希望我们将继续收集癌症患者的样本，并通过使用IL-18开发癌症免疫疗法。