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

为了阐明白细胞介素18 （IL-18）的抗肿瘤作用，本文在小鼠肿瘤模型中分析了IL-18的作用机制。我们发现NK细胞而非NKT细胞在促进IL-18诱导的先天抗肿瘤反应中发挥必要的作用。此外，我们假设IL-18在小鼠肿瘤模型中诱导的抗肿瘤特异性免疫是通过增强nk介导的肿瘤破坏和向树突状细胞（dc）的递送来促进的。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，发现IL-18通过增强NK细胞活性诱导肿瘤特异性免疫，进而介导肿瘤细胞死亡并激活和启动dc。接下来，我们研究了IL-18和IL-2联合使用对人淋巴细胞的体外影响。这两种细胞因子的联合使用协同增强了IFN-γ的产生。表型分析显示CD56+ CD3- (NK)细胞优先扩增。为了揭示被IL-18激活的人淋巴细胞诱导肿瘤凋亡，我们将肿瘤细胞与IL-18激活的淋巴细胞培养8小时后用Annexin-V、PhiPhiLux或PI染色。联合使用这些细胞因子可观察到肿瘤细胞的凋亡。这些结果表明IL-18在人体系统中具有抗肿瘤作用。因此，联合使用IL-2和IL-18应该被认为是在体内产生抗肿瘤反应和未来临床应用的可行策略。

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.