免疫抑制性细胞Treg/Th17、MDSCs在胃癌发生发展中作用的临床研究
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摘要
目的CD4~+CD25~+Foxp3~+Treg、Th17及单核样髓源性抑制细胞(MDSCs)被认为是最为关键的参与肿瘤免疫逃逸机制的细胞。本研究检测Treg/Th17、MDSCs在胃癌患者外周血中表达变化，以初步探讨CD4~+CD25~+Foxp3~+Treg、Th17及MDSCs在胃癌发生发展中的作用。
方法收集77例胃癌、21例胃上皮内瘤变、31例萎缩性胃炎、45例胃溃疡、20例正常对照外周血，流式细胞仪分析CD4~+CD25~+Foxp3~+Treg表达，PMA+Ionomycin联合刺激后，流式细胞仪检测CD4+IL-17+Th17表达，结合临床资料初步分析Treg及Th17表达与胃癌患者年龄、性别、肿瘤生长部位、临床TNM分期、浸润深度及淋巴结转移的相关性；流式细胞仪检测循环单核样MDSCs占单核样细胞百分比，并初步探讨MDSCs与胃癌患者年龄、性别、肿瘤生长部位、临床TNM分期、浸润深度及淋巴结转移的相关性。
结果（1）外周血CD4~+CD25~+Foxp3~+Treg细胞占CD4~+T细胞百分比分别为胃癌患者（4.72±1.01）%、胃上皮内瘤变（3.23±0.38）%、萎缩性胃炎（2.57±0.41）%、胃溃疡（2.02±0.63）%、及正常对照（1.57±0.99）%，胃癌患者Treg细胞表达水平较胃上皮内瘤变、萎缩性胃炎、胃溃疡及正常对照组明显升高，统计学显示各组之间均具有显著差异（P<0.01）。外周血Th17占CD4~+T细胞百分比分别为胃癌患者（8.16±3.13）%、胃上皮内瘤变（6.80±2.12）%、萎缩性胃炎（5.79±1.40）%、胃溃疡（4.94±1.06）%及正常对照组（4.85±1.85）%，胃癌患者外周血中Th17所占比例较胃上皮内瘤变组、萎缩性胃炎组、胃溃疡组及正常对照组明显升高，统计学显示各组之间均具有显著差异（P<0.01），胃癌患者外周血中Treg细胞表达水平与胃癌临床分期、肿瘤浸润深度及淋巴结转移有关，但与患者性别、年龄、肿瘤生长部位无关；Th17与胃癌患者年龄、性别、临床分期、浸润深度及淋巴结转移均无相关性。（2）外周血MDSCs占单核样细胞百分比分别为胃癌患者（21.72±10.12）%、胃上皮内瘤变（13.16±3.79）%、萎缩性胃炎（7.74±1.14）%、胃溃疡（4.79±1.07）%及正常对照组（2.90±1.80）%，胃癌患者较其余各组外周血MDSC细胞呈高表达状态，统计学显示各组之间均具有显著差异（P<0.01）；进展期胃癌（IIA、IIB、IIIA、IIIB、IIIC、IV期）MDSCs（23.79±9.48）%较早期胃癌（IA、IB期）MDSCs（11.74±4.01）%水平明显升高（P<0.05）；MDSCs比例与胃癌患者年龄、性别、肿瘤浸润深度、淋巴结转移均无相关性。（3）外周血MDSCs与Treg（r=0.681）及Th17（r=0.724）呈正相关。
结论（1）胃癌患者外周血存在Treg及Th17细胞高表达现象，提示胃癌患者可能存在Treg/Th17平衡紊乱。(2)胃癌患者外周血MDSCs水平明显升高，可能与胃癌免疫功能低下和胃癌发生发展密切相关。
Objective CD4~+CD25~+Foxp3~+Treg, Th17and myeloid-derived suppressor cells(MDSCs) are considered to be the most critical cells participating in tumor immune escapemechanism. This studies were detected the changes of Treg/Th17, MDSCs expressions inthe peripheral blood of patients with gastric cancer, to preliminary approach to the role ofCD4~+CD25~+Foxp3~+Treg, Th17, MDSCs in the development and progression of the gastriccancer.
Methods The peripheral blood specimens from77cases gastric cancer,21cases gastricintraepithelial neoplasia,33cases atrophic gastritis,45cases gastric ulcer and20caseshealthy controls were collected. The CD4~+CD25~+Foxp3~+Treg expressions were measuredby flow cytometry, and the CD4+IL-17+Th17expressions after the co-stimulation of PMAand Ionomycin were also measured by flow cytometry The correlations between the Tregand Th17expressions with age, sex, tumor location, TNM stage, depth of invasion andlymph node metastasis of gastric cancer were preliminary analyzed based on the clinicaldata. The peripheral blood mononuclear MDSCs percentage were measure by flowcytometry, and the correlation between the MDSCs with age, sex, tumor location, TNMstage, depth of invasion and lymph node metastasis of gastric cancer were preliminaryanalyzed.
Results (1) The peripheral blood percentage CD4~+CD25~+Foxp3~+Treg cells of CD4+T cell in gastric cancer[（4.72±1.01）%] was significantly higher than in gastricintraepithelial neoplasia[(3.23±0.38)%], in atrophic gastritis[(2.57±0.41)%], in gastriculcer [(2.02±0.63)%], in healthy controls[（1.57±0.99）%](p<0.01), and were showedstatistically significantly difference among the five groups(p<0.01). The peripheral bloodTh17percentage of CD4~+T cells in gastric cancer[（8.16±3.13）%]was significantlyhigher than in gastric intraepithelial neoplasia[(6.80±2.12)%], in atrophic gastritis[(5.79±1.40)%], in gastric ulcer[(4.94±1.06)%] and in healthycontrols[(4.85±1.85)%], and were showed statistically significantly difference among thefive groups(p<0.01). The peripheral blood percentage CD4~+CD25~+Foxp3~+Treg cells ofCD4~+T cell in gastric cancer patients were correlated to the depth of infiltration,lymphatic metastasis, and clinical TNM stages, but were no related to the age, gender andtumor location. The peripheral blood Th17percentage of CD4~+T cells in gastric cancerpatients were no related with the age, gender, clinical TNM stages, depth of infiltration,and lymphatic metastasis.
(2) The peripheral blood mononuclear MDSCs percentage in gastriccancer[（21.72±10.12）%] were significantly higher than in gastric intraepithelialneoplasia[(13.16±3.79)%], in atrophic gastritis[(7.74±1.14)%], in gastric ulcer[(4.79±1.07)%], in healthy controls[（2.90±1.80）%], and were showed statisticallysignificantly difference among the five groups(p<0.01). The peripheral blood mononuclearMDSCs percentage in advanced gastric cancer （IIA, IIB, IIIA, IIIB, IIIC,IVstage)[（23.79±9.48）%] was significantly higher than in early gastric cancer（IA, IBstage）[（11.74±4.01）%](P<0.05), but were no related with the age, gender, depth ofinfiltration, and lymphatic metastasis in gastric cancer patients.
(3)The peripheral blood mononuclear MDSCs percentage were showed positiverelation to the peripheral blood percentage CD4~+CD25~+Foxp3~+Treg cells of CD4+Tcell(r=0.680) and the peripheral blood Th17percentage of CD4~+T cells(r=0.724).
Conclusion (1) Gastric cancer patients may exist the high Treg and Th17cellsexpressions in peripheral blood, That suggested there is a disturbance of Treg/Th17ingastric cancer.(2) The peripheral blood mononuclear MDSCs percentage in gastric cancerpatients is remarkable rise, which may be related with low immune function of gastriccancer and development in the gastric cancer
方法收集77例胃癌、21例胃上皮内瘤变、31例萎缩性胃炎、45例胃溃疡、20例正常对照外周血，流式细胞仪分析CD4~+CD25~+Foxp3~+Treg表达，PMA+Ionomycin联合刺激后，流式细胞仪检测CD4+IL-17+Th17表达，结合临床资料初步分析Treg及Th17表达与胃癌患者年龄、性别、肿瘤生长部位、临床TNM分期、浸润深度及淋巴结转移的相关性；流式细胞仪检测循环单核样MDSCs占单核样细胞百分比，并初步探讨MDSCs与胃癌患者年龄、性别、肿瘤生长部位、临床TNM分期、浸润深度及淋巴结转移的相关性。
结果（1）外周血CD4~+CD25~+Foxp3~+Treg细胞占CD4~+T细胞百分比分别为胃癌患者（4.72±1.01）%、胃上皮内瘤变（3.23±0.38）%、萎缩性胃炎（2.57±0.41）%、胃溃疡（2.02±0.63）%、及正常对照（1.57±0.99）%，胃癌患者Treg细胞表达水平较胃上皮内瘤变、萎缩性胃炎、胃溃疡及正常对照组明显升高，统计学显示各组之间均具有显著差异（P<0.01）。外周血Th17占CD4~+T细胞百分比分别为胃癌患者（8.16±3.13）%、胃上皮内瘤变（6.80±2.12）%、萎缩性胃炎（5.79±1.40）%、胃溃疡（4.94±1.06）%及正常对照组（4.85±1.85）%，胃癌患者外周血中Th17所占比例较胃上皮内瘤变组、萎缩性胃炎组、胃溃疡组及正常对照组明显升高，统计学显示各组之间均具有显著差异（P<0.01），胃癌患者外周血中Treg细胞表达水平与胃癌临床分期、肿瘤浸润深度及淋巴结转移有关，但与患者性别、年龄、肿瘤生长部位无关；Th17与胃癌患者年龄、性别、临床分期、浸润深度及淋巴结转移均无相关性。（2）外周血MDSCs占单核样细胞百分比分别为胃癌患者（21.72±10.12）%、胃上皮内瘤变（13.16±3.79）%、萎缩性胃炎（7.74±1.14）%、胃溃疡（4.79±1.07）%及正常对照组（2.90±1.80）%，胃癌患者较其余各组外周血MDSC细胞呈高表达状态，统计学显示各组之间均具有显著差异（P<0.01）；进展期胃癌（IIA、IIB、IIIA、IIIB、IIIC、IV期）MDSCs（23.79±9.48）%较早期胃癌（IA、IB期）MDSCs（11.74±4.01）%水平明显升高（P<0.05）；MDSCs比例与胃癌患者年龄、性别、肿瘤浸润深度、淋巴结转移均无相关性。（3）外周血MDSCs与Treg（r=0.681）及Th17（r=0.724）呈正相关。
结论（1）胃癌患者外周血存在Treg及Th17细胞高表达现象，提示胃癌患者可能存在Treg/Th17平衡紊乱。(2)胃癌患者外周血MDSCs水平明显升高，可能与胃癌免疫功能低下和胃癌发生发展密切相关。
Objective CD4~+CD25~+Foxp3~+Treg, Th17and myeloid-derived suppressor cells(MDSCs) are considered to be the most critical cells participating in tumor immune escapemechanism. This studies were detected the changes of Treg/Th17, MDSCs expressions inthe peripheral blood of patients with gastric cancer, to preliminary approach to the role ofCD4~+CD25~+Foxp3~+Treg, Th17, MDSCs in the development and progression of the gastriccancer.
Methods The peripheral blood specimens from77cases gastric cancer,21cases gastricintraepithelial neoplasia,33cases atrophic gastritis,45cases gastric ulcer and20caseshealthy controls were collected. The CD4~+CD25~+Foxp3~+Treg expressions were measuredby flow cytometry, and the CD4+IL-17+Th17expressions after the co-stimulation of PMAand Ionomycin were also measured by flow cytometry The correlations between the Tregand Th17expressions with age, sex, tumor location, TNM stage, depth of invasion andlymph node metastasis of gastric cancer were preliminary analyzed based on the clinicaldata. The peripheral blood mononuclear MDSCs percentage were measure by flowcytometry, and the correlation between the MDSCs with age, sex, tumor location, TNMstage, depth of invasion and lymph node metastasis of gastric cancer were preliminaryanalyzed.
Results (1) The peripheral blood percentage CD4~+CD25~+Foxp3~+Treg cells of CD4+T cell in gastric cancer[（4.72±1.01）%] was significantly higher than in gastricintraepithelial neoplasia[(3.23±0.38)%], in atrophic gastritis[(2.57±0.41)%], in gastriculcer [(2.02±0.63)%], in healthy controls[（1.57±0.99）%](p<0.01), and were showedstatistically significantly difference among the five groups(p<0.01). The peripheral bloodTh17percentage of CD4~+T cells in gastric cancer[（8.16±3.13）%]was significantlyhigher than in gastric intraepithelial neoplasia[(6.80±2.12)%], in atrophic gastritis[(5.79±1.40)%], in gastric ulcer[(4.94±1.06)%] and in healthycontrols[(4.85±1.85)%], and were showed statistically significantly difference among thefive groups(p<0.01). The peripheral blood percentage CD4~+CD25~+Foxp3~+Treg cells ofCD4~+T cell in gastric cancer patients were correlated to the depth of infiltration,lymphatic metastasis, and clinical TNM stages, but were no related to the age, gender andtumor location. The peripheral blood Th17percentage of CD4~+T cells in gastric cancerpatients were no related with the age, gender, clinical TNM stages, depth of infiltration,and lymphatic metastasis.
(2) The peripheral blood mononuclear MDSCs percentage in gastriccancer[（21.72±10.12）%] were significantly higher than in gastric intraepithelialneoplasia[(13.16±3.79)%], in atrophic gastritis[(7.74±1.14)%], in gastric ulcer[(4.79±1.07)%], in healthy controls[（2.90±1.80）%], and were showed statisticallysignificantly difference among the five groups(p<0.01). The peripheral blood mononuclearMDSCs percentage in advanced gastric cancer （IIA, IIB, IIIA, IIIB, IIIC,IVstage)[（23.79±9.48）%] was significantly higher than in early gastric cancer（IA, IBstage）[（11.74±4.01）%](P<0.05), but were no related with the age, gender, depth ofinfiltration, and lymphatic metastasis in gastric cancer patients.
(3)The peripheral blood mononuclear MDSCs percentage were showed positiverelation to the peripheral blood percentage CD4~+CD25~+Foxp3~+Treg cells of CD4+Tcell(r=0.680) and the peripheral blood Th17percentage of CD4~+T cells(r=0.724).
Conclusion (1) Gastric cancer patients may exist the high Treg and Th17cellsexpressions in peripheral blood, That suggested there is a disturbance of Treg/Th17ingastric cancer.(2) The peripheral blood mononuclear MDSCs percentage in gastric cancerpatients is remarkable rise, which may be related with low immune function of gastriccancer and development in the gastric cancer
引文
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