上皮性卵巢癌患者血清IL-37变化与免疫抑制相关因子关联分析

Correlation between serum IL-37 and immunosuppression related factors in patients with epithelial ovarian cancer

目的上皮性卵巢癌(epithelial ovarian cancer,EOC)病因学与免疫炎症相关,近期发现白细胞介素37(interleukin-37,IL-37)作为抑炎性细胞因子在多种肿瘤中异常表达,但在EOC中罕见报道。本研究探讨EOC患者血清IL-37的变化及其与临床病理学特征、血管内皮生长因子(vascular endothelial growth factor,VEGF)、免疫检查点分子可溶性程序性死亡蛋白1(soluble programmed cell death protein 1,sPD-1)及免疫抑制细胞调节性T细胞(regulatory T cells,Treg)的相关性。方法选取2016-07-09-2019-02-17九江市第一人民医院53例病理学确诊的EOC初诊患者,同时选取50名同期健康体检人群作为对照组。酶联免疫吸附试验(enzyme-linked immunosorbent assay,ELISA)测定血清IL-37、基质金属蛋白酶-9(matrix metalloproteinase-9,MMP-9)、VEGF及sPD-1的浓度,流式细胞术检测外周血Treg细胞频率。IL-37与各指标间的相关性采用Spearman相关分析。结果EOC组患者血清IL-37、MMP-9、VEGF和sPD-1表达水平分别为(375.42±107.20)pg/mL和(453.67±176.15)、(41.40±17.64)、(2.42±1.01)ng/mL,均高于对照组的(150.66±29.02)pg/mL和(295.74±121.12)、(8.69±4.07)、(0.84±0.41)ng/mL,差异有统计学意义,均P<0.001。EOC组患者外周血Treg细胞频率为(8.78±3.07)%,高于对照组的(2.66±1.04)%,差异均有统计学意义,t=13.493,P<0.001。IL-37在不同年龄EOC患者中差异无统计学意义(t=0.378,P=0.707),而与肿瘤大小、淋巴结转移与否及FIGO分期密切相关。血清IL-37与sPD-1(r=0.346,P=0.011)和Treg细胞频率(r=0.446,P<0.001)间均呈正相关,而与MMP-9和VEGF相关性不显著。结论IL-37在EOC患者血清中异常上调,与肿瘤进展和免疫抑制相关因子存在关联。

OBJECTIVE The etiology of epithelial ovarian cancer(EOC)is related to immune system.Interleukin-37(IL-37)has been found to be abnormally expressed as an anti-inflammatory cytokine in many tumors,but it has not been reported in EOC.The aim of this study was to investigate the changes of serum IL-37 in patients with EOC and its association with clinicopathological characteristics,matrix metalloproteinase-9(MMP-9),vascular endothelial growth factor(VEGF),soluble programmed cell death protein 1(sPD-1)and regulatory T cells(Treg).METHODS Fifty-three patients with EOC diagnosed by pathology and histology were divided into stagesⅠ,Ⅱ,ⅢandⅣaccording to FIGO staging criteria,and 50 healthy people in the same period were selected as control group.Enzyme-linked immunosorbent assay(ELISA)was used to determine the serum levels of IL-37,MMP-9,VEGF and sPD-1 in EOC patients and control groups.The frequency of Treg cells in peripheral blood was detected by flow cytometry.The correlation between IL-37 and other indices was analyzed by Spearman method.RESULTS The serum levels of IL-37,MMP-9,VEGF and sPD-1 in EOC patients were(375.42±107.20)pg/ml,(453.67±176.15)ng/ml,(41.40±17.64)ng/ml and(2.42±1.01)ng/ml,which were higher than those in healthy controls[150.66±29.02)pg/ml,(295.74±121.12)ng/ml,(8.69±4.07)ng/ml and(0.84±0.41)ng/ml].The frequency of Treg cells in peripheral blood was also significantly increased[(8.78±3.07)%vs(2.66±1.04)%,t=13.493,P<0.001].In addition,IL-37 were closely related to tumor size,lymph node metastasis and FIGO stages,while there was no significant difference among EOC patients of different ages(t=0.378,P=0.707).In addition,serum IL-37 was positively correlated with the level of sPD-1(r=0.346,P=0.011)and frequency of Treg cells(r=0.446,P<0.001),but not with MMP-9 and VEGF.CONCLUSION IL-37 is abnormally up-regulated in serum of EOC patients,which is associated with tumor progression and immunosuppressive factors.