非小细胞肺癌患者外周血中HIF-1α^+MDSC比例对低氧条件下CD8^+T细胞杀伤活性的影响  

Effects of HIF-1α^+MDSC proportion in peripheral blood from NSCLC patients on cytotoxic activity of CD8^+T cells under hypoxia condition

作　　者：李洁瑶[1] 张毅[2] 王丽萍[1] LI Jieyao;ZHANG Yi;WANG Liping(Department of Oncology,the First Affiliated Hospital,Zhengzhou University,Zhengzhou 450052;Biotherapy Center,the First Affiliated Hospital,Zhengzhou University,Zhengzhou 450052)

机构地区：[1]郑州大学第一附属医院肿瘤中心,郑州450052 [2]郑州大学第一附属医院生物细胞治疗中心,郑州450052

出　　处：《郑州大学学报（医学版）》2020年第2期182-186,共5页Journal of Zhengzhou University(Medical Sciences)

基　　金：国家自然科学基金面上项目(81872410);国家自然科学基金青年项目(81702812);河南省卫健委科技攻关项目(201702048)。

摘　　要：目的:非小细胞肺癌患者外周血中HIF-1α^+髓源抑制细胞(MDSC)比例对低氧条件下CD8^+T细胞杀伤活性的影响。方法:采用流式细胞术检测35例非小细胞肺癌患者及29名健康人(正常对照)外周血中HIF-1α^+MDSC(M-MDSC和G-MDSC)的比例,分析非小细胞肺癌患者外周血中HIF-1α^+MDSC比例与非小细胞肺癌患者临床参数和疗效的关系。利用体外培养技术共孵育NSCLC患者HIF-1α^+MDSC和正常CD8^+T细胞,分为加入和不加入HIF-1α抑制剂组,采用流式细胞术检测HIF-1α^+MDSC与CD8^+T细胞孵育比例和HIF-1α抑制剂对CD8^+T细胞分泌颗粒酶B和穿孔素水平的影响。结果:①非小细胞肺癌患者外周血中HIF-1α^+G-MDSC和HIF-1α^+M-MDSC比例均高于正常对照(P<0.05)。②HIF-1α^+MDSC比例与淋巴结转移、临床分期及肿瘤分化程度有关(P<0.05)。③化疗前HIF-1α^+MDSC比例高者疗效差(P=0.026)。④HIF-1α^+G-MDSC和HIF-1α^+M-MDSC均可抑制CD8^+T细胞分泌颗粒酶B和穿孔素的能力,其抑制作用呈一定的剂量依赖性;HIF-1α抑制剂可增强CD8^+T细胞分泌颗粒酶B和穿孔素的能力(P<0.05)。结论:非小细胞肺癌患者外周血中HIF-1α^+MDSC比例与预后有关,HIF-1α^+MDSC可抑制低氧条件下CD8^+T细胞的杀伤活性,可作为评价预后的指标及肿瘤治疗的新靶点。Aim:To observe the effects of HIF-1α^+myeloid-derived suppressor cells(MDSC)proportion in peripheral blood from non-small cell lung cancer(NSCLC)patients on cytotoxic activity of CD8^+T cells under hypoxia condition.Methods:Peripheral blood was obtained from 35 patients with NSCLC and 29 healthy donors.The proportion of HIF-1α^+MDSC(M-MDSC and G-MDSC)was determined by flow cytometry.The relationship between HIF-1α^+MDSC proportions with clinical parameters and clinical efficacy was analyzed.In vitro,purified MDSCs from NSCLC patients were incubated with CD8^+T cells from a normal control in the absence or presence of HIF-1αinhibitor.The production of granzyme B and perforin by CD8^+T cells was determined by flow cytometry.Results:It was revealed that HIF-1α^+G-MDSC and HIF-1α^+M-MDSC proportions of NSCLC patients were higher than those of healthy donors(P<0.05).The proportion of HIF-1α^+MDSC was positively related with lymph node metastasis,tumor stage,and differentiation degree(P<0.05).The patients with high level of HIF-1α^+MDSC proportion showed poor response to chemotherapy(P=0.026).Both HIF-1α^+G-MDSC and HIF-1α^+M-MDSC could inhibit the production of granzyme B and perforin by CD8^+T cells and the suppression was dose-dependent;in the presence of HIF-1αinhibitor,the function of CD8^+T cells secreting granzyme B and perforin was increased(P<0.05).Conclusion:HIF-1α^+MDSC proportion in peripheral blood from NSCLC patients is associated with prognosis of the patients;HIF-1α^+MDSC could inhibit cytotoxic activity of CD8^+T cells under hypoxia condition,and thus could be used as a prognostic index and novel targets for cancer treatment.

关 键 词：非小细胞肺癌 髓源抑制细胞 低氧诱导因子-1Α 化疗 

分 类 号：R734.2[医药卫生—肿瘤]