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

我们在海洋和人体模型中研究了IL-18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凋亡。此外，肿瘤凋亡通过树突状细胞诱导肿瘤特异性细胞毒性T淋巴细胞（CTL）。我们研究了IL-18和IL-2联合使用对人外周血单个核细胞的抗肿瘤作用。这两种细胞因子的结合产生了大量的IFN-γ，并增强了肿瘤细胞对肿瘤细胞系的死亡。此外，表型分析显示CD56+ CD161+ CD3-NK细胞在PBMC上扩增。在本项目中，我们详细研究了IL-18在人体模型中的抗肿瘤作用。我们发现肿瘤细胞与IL-2和IL-18激活的PBMC共培养可诱导人鳞状细胞癌细胞凋亡。接下来，我们利用RT - PCR检测了TRAIL和FasL在IL-18刺激的PBMC上的表达，发现IL-18刺激后TRAIL和FasL mRNA表达上调。这些结果表明TRAIL和FasL在il -18诱导的肿瘤凋亡中起关键作用。接下来，我们分析了IL-18对口腔癌患者PBMC的反应。我们收集患者化疗前后的PBMC，观察NK或T细胞的变化。在本研究中，我们已向东北大学医院委员会提出临床申请，并获得批准。然后，我们开始收集临床样本，得到了一些样本。但我们无法分析数据，因为样本数量不多。我们希望我们将继续收集癌症患者的样本，并利用IL-18开发癌症免疫疗法。

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.