巨噬细胞浸润在低级别胶质瘤预后预测中的研究

Macrophages infiltration in low grade glioma and its value in prognosis prediction

目的检测肿瘤相关性巨噬细胞(TAM)在低级别胶质瘤(LGG)分子亚型中的浸润程度和功能状态,分析TAM相关指标在LGG患者预后预测中的价值。方法获取癌症基因组图谱(TCGA)中529例LGG数据,比较TAM浸润指标在IDH 1/2野生型低级别胶质瘤(IDH 1/2-wt LGG)和IDH 1/2突变型低级别胶质瘤(IDH 1/2-mu LGG)中的表达水平,分析CD163和IL-10在LGG患者预后预测中的价值。利用免疫组化法检测本中心17例IDH 1/2-wt和19例IDH 1/2-mu LGG临床样本中TAM的浸润数量。使用Mann-Whitney U检验,COX回归和Kaplan-Meier法进行统计学分析。结果 TCGA数据分析表明,IDH 1/2-wt LGG中巨噬细胞和TAM标记物CD68(Mann-Whitney U=19 425,P=0.01)、CD11b(Mann-Whitney U=15 836,P<0.01)、IBA1(Mann-WhitneyU=17 758,P<0.01)、CD163(Mann-Whitney U=18 112,P <0.01)、CD204(Mann-Whitney U=12 676,P <0.01)以及TAM趋化因子CCL2(Mann-WhitneyU=15 841,P<0.01)、CCL5(Mann-WhitneyU=11 326,P<0.01)、POSTN(Mann-Whitney U=8 893,P <0.01)、VEGF-A(Mann-Whitney U=14 433,P <0.01)、Neurotensin(Mann-Whitney U=15 556,P <0.01)的表达水平高于IDH 1/2-mu LGG。本中心免疫组化提示TAM在IDH 1/2-wt组中的浸润数量高于IDH 1/2-mu组(Mann-Whitney U=51,P<0.01;Mann-WhitneyU=35,P<0.01;Mann-WhitneyU=20,P<0.01)。IDH 1/2-wt LGG较IDH 1/2-muLGG表达更多的免疫抑制因子TGF-β(Mann-Whitney U=15 459,P <0.01)和IL-10(Mann-Whitney U=17 334,P <0.01)。生存分析结果表明,CD163^(high)IDH-wt LGG患者的预后较CD163^(low)IDH-wt LGG患者差(P=0.01),IL-10^(high)IDH-mu LGG患者预后较IL-10^(low)IDH-mu LGG患者差(P <0.05)。结论 IDH 1/2-wt LGG和IDH 1/2-mu LGG中TAM的浸润数量及免疫抑制状态存在差异;TAM标志物CD163表达水平与IDH 1/2-wt LGG患者预后负相关,TAM相关免疫抑制因子IL-10表达水平与IDH 1/2-mu LGG患者的预后负相关。

Objective To detect the infiltration degree and functional state of tumorassociated macrophages(TAM)in different low-grade glioma(LGG)subtypes,and to analyze the value of TAM related biomarkers in predicting patient prognosis.Methods We downloaded 529 cases LGG data from The Cancer Genome Atlas(TCGA),and compared the expression levels of TAM infiltration biomarkers between IDH 1/2-wt LGG and IDH 1/2-mu LGG.CD163 and IL-10 were used to predict patient prognosis.We also detected the infiltration degree of TAM by immunohistochemistry in 17 IDH 1/2-wt and 19 IDH 1/2-mu LGG clinical samples.Mann-Whitney U test,COX regression and Kaplan-Meier method were used for statistical analysis.Results TCGA data analysis showed that the expression levels of macrophages and TAM markers CD68(Mann-Whitney U=19425,P=0.01),CD11b(Mann-Whitney U=15836,P<0.01),IBA1(Mann-Whitney U=17758,P<0.01),CD163(Mann-Whitney U=18112,P<0.01),CD204(Mann-Whitney U=12676,P<0.01)in IDH 1/2-wt LGG were significantly higher than IDH 1/2-mu LGG.Meanwhile,the infiltration degree of TAM in clinical glioma tissues was higher in IDH 1/2-wt LGG compared to IDH 1/2-mu LGG(Mann-Whitney U=51,P<0.01;Mann-Whitney U=35,P<0.01;Mann-Whitney U=20,P<0.01).IDH 1/2-wt LGG expressed more TAM chemokines CCL2(Mann-Whitney U=15841,P<0.01),CCL5(Mann-Whitney U=11 326,P<0.01),POSTN(Mann-Whitney U=8 893,P<0.01),VEGF-A(Mann-Whitney U=14433,P<0.01),Neurotensin(Mann-Whitney U=15 556,P<0.01)than IDH 1/2-mu LGG.Additionally,the expression levels of TGF-β(Mann-Whitney U=15 459,P<0.01)和IL-10(Mann-Whitney U=17 334,P<0.01)produced by TAM were significantly up-regulated in IDH 1/2-wt LGG.Furthermore,survival analysis showed that in the IDH 1/2-wt group,the overall survival rate of the CD163^high patients was lower than the CD163^low patients(P=0.01),and the overall survival rate of the IL-10^high patients was lower than IL-10^low patients in the IDH 1/2-mu LGG patients(P<0.05).Conclusion The infiltration numbers of TAM and immunosuppression states are different between IDH 1/2-wt LGG and IDH 1/2-mu LGG.The expression level of CD163 is negatively correlated with prognosis of IDH 1/2-wt LGG patients,and the expression level of IL-10 is negatively correlated with prognosis of IDH 1/2-mu LGG patients.