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

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激活自然杀伤细胞和诱导肿瘤细胞凋亡的作用。此外，肿瘤细胞的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)。这两种细胞因子的结合产生了大量的干扰素-γ，并增强了肿瘤细胞对肿瘤细胞的杀伤作用。此外，表型分析显示CD56+CD161+CD3-NK细胞在PBMC上扩增。在本项目中，我们详细地研究了IL-18在人体模型中的抗肿瘤作用。我们发现，与肿瘤细胞以及IL-2和IL-18激活的PBMC共同培养可以诱导人鳞癌细胞系的肿瘤细胞凋亡。接下来，我们用RT-PCR检测了IL-18刺激的PBMC上TRAIL和FasL的表达，发现IL-18刺激后TRAIL和FasL的mRNA表达上调。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。采集患者化疗前、后外周血单个核细胞，观察NK、T细胞的变化。在本研究中，我们已向东北大学医院委员会申请临床应用，并获得批准。然后，我们已经开始收集临床样本，并获得了一些样本。但我们无法分析数据，因为样本数量并不多。我们希望继续从癌症患者身上采集样本，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.