阻断EGFR影响肺鳞癌肿瘤微环境Treg细胞及IL-1A表达

发布时间：2018-07-25 16:23

【摘要】：背景与目的精确靶向表皮生长因子受体(epidermal growth factor receptor,EGFR)的治疗在肺鳞癌、口腔和肠胃癌中取得了一定疗效,但会引发系统性炎症。本实验旨在探究EGFR抑制剂治疗癌引发的肿瘤内部免疫变化。方法我们通过含H-ras基因逆转录病毒转染EGFR基因缺失或野生型小鼠角质细胞,将改造的细胞同源移植至小鼠以成瘤,吉非替尼治疗荷瘤小鼠,流式细胞仪检测T细胞比例与程序性死亡受体1(programmed death 1,PD-1)表达,RT-PCR检测细胞因子与趋化因子的表达。结果敲除EGFR基因形成的肿瘤较野生型小,并且肿瘤微环境中浸润FoxP3+调节性T细胞(regulatory cells,Treg)细胞较少,FoxP3 RNA较少,程序性死亡受体1(programmed death 1,PD-1)阳性CD4~+细胞比例降低。表明肿瘤细胞可以自主调节肿瘤微环境。野生型成瘤模型使用吉非替尼治疗1周显示,相对于对照组肿瘤较小;在这短期的药理模型中,同样观察到FoxP3+细胞、FoxP3 RNA减少的趋势,同时IL-1A/IL-1RA比例明显升高,表明相对短暂的系统性抑制EGFR信号通路可改变靶向肿瘤的免疫微环境。结论肿瘤细胞自发(基因)或系统性(药理作用)的抑制EGFR信号通路可减少肿瘤的生长和肿瘤微环境中Treg的渗透。EGFR依赖性Treg细胞增强肺鳞癌的生长,是EGFR抑制剂治疗的靶标。
[Abstract]:Background & objective Epidermal growth factor receptor (epidermal growth factor receptor (EGFR) has been successfully targeted for the treatment of squamous cell carcinoma of the lung, oral cavity and stomach cancer, but it can cause systemic inflammation. The aim of this study was to investigate the internal immune changes in cancer induced by EGFR inhibitors. Methods the keratinocytes of mice with EGFR gene deletion or wild-type were transfected with retrovirus containing H-ras gene. The transformed cells were homologous transplanted to mice for tumorigenesis. Gifitinib was used to treat tumor-bearing mice. The expression of T cell and PD-1 was detected by flow cytometry. RT-PCR was used to detect the expression of cytokines and chemokines. Results the number of EGFR gene knockout was smaller than that of wild type, and the number of regulatory cells infiltrating regulatory T cells (regulatory cells) in microenvironment was less, and the percentage of positive CD4~ cells of programmed death receptor 1 (programmed death 1 (PD-1) was decreased. These results suggest that tumor cells can regulate tumor microenvironment autonomously. In the wild-type tumor-forming model treated with gefitinib for one week, the tumor was smaller than that in the control group. In this short-term pharmacological model, the decrease of FoxP3 RNA in FoxP3 cells was also observed, and the IL-1A/IL-1RA ratio was significantly increased. It is suggested that relatively transient systemic inhibition of EGFR signaling pathway can change the immune microenvironment of targeted tumors. Conclusion inhibition of EGFR signaling pathway by tumor cells spontaneously (gene) or systemic (pharmacological) can reduce tumor growth and enhance the growth of lung squamous cell carcinoma by Treg osmotic. EGFR-dependent Treg cells in tumor microenvironment. It is a target of EGFR inhibitor therapy.
【作者单位】：武警后勤学院;武警后勤学院附属医院;
【基金】：全军重点实验室开放基金项目(No.JY1406)资助
【分类号】：R734.2

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