阻断EGFR影响肺鳞癌肿瘤微环境Treg细胞及IL-1A表达  

Altered Treg and IL-1A Expression in the Immune Microenvironment of Lung Squamous-cell Cancer after EGFR Blockade

作　　者：何海洋[1] 齐陆玉 侯伊玲[2] 

机构地区：[1]武警后勤学院,天津300162 [2]武警后勤学院附属医院,天津300162

出　　处：《中国肺癌杂志》2017年第3期143-148,共6页Chinese Journal of Lung Cancer

基　　金：全军重点实验室开放基金项目(No.JY1406)资助

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。Background and objective Targeting the mutations and amplifications in the epidermal growth factor receptor（EGFR） gene has curative effects on cancers of the lung,oral cavity,and gastrointestinal system.However,a systemic immune inflammation is an adverse effect of this therapeutic strategy.In this study,we aimed to identify the possible changes in the tumor microenvironment that contribute to the anti-cancer activity of EGFRinhibition.Methods Squamous-cell cancers were induced by the syngeneic transplantation of either EGFR-null or wild-type mouse primary keratinocytes that had been transduced with an oncogenic H-ras retrovirus,The mice were treated with gefinitib,Then,flow cytometric was used to detect the ratio of T cells and the expression of programmed cell death receptor 1（PD-1）.RT-PCR was used to detect the expression of cytokines and chemokines.Results Tumors that formed from EGFR-null keratinocytes were smaller,had fewer infiltrating FoxP3＋ Treg cells,lower Foxp3 RNA,and lower percentage of PD-1 positive CD4 cells than those formed from wild-type keratinocytes,These results indicated that tumor cells can autonomously regulate the tumor microenvironment.Hosts with wild-type cancers and that were treated with gefitinib for 1 week tended to have smaller tumors,The treated mice in the shortterm pharmacological model tended to have reduced FoxP3＋ cells and FoxP3 RNA in the tumor microenvironment,as well as a substantially increased ratio of IL-1A/IL-1RA transcripts,These results suggested that the brief systemic inhibition of EGFR signaling alters the immune environment of the targeted cancer.Conclusion The autonomous（genetic） or systemic（pharmacologic） inhibition of EGFR signaling in tumor cells reduces tumor growth and Treg infiltration in the tumor microenvironment.An EGFR-dependent Treg function supports the growth of squamous cancers,Therefore,Treg is a target in the therapeutic strategy of EGFR inhibition.

关 键 词：EGFR 肺肿瘤 吉非替尼 肿瘤免疫微环境 TREG 

分 类 号：R734.2[医药卫生—肿瘤]