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中华细胞与干细胞杂志(电子版)

中华细胞与干细胞杂志(电子版) ›› 2018, Vol. 08 ›› Issue (04) : 204 -211. doi: 10.3877/cma.j.issn.2095-1221.2018.04.003

所属专题： 文献；

论著

巨噬细胞浸润在低级别胶质瘤预后预测中的研究
马健行1, 吴鹏飞1, 杨伟1, 廖茂君1, 易良1, 许民辉1,†()   
  1. 1. 400042　重庆，陆军军医大学第三附属医院神经外科
  • 收稿日期:2018-03-26 出版日期:2018-08-01
  • 通信作者: 许民辉
  • 基金资助:
    国家自然科学基金(81772662、81300965); 重庆市自然基金基础研究与前沿探索项目(cstc2018jcyjAX0600)

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

Jianxing Ma1, Pengfei Wu1, Wei Yang1, Maojun Liao1, Liang Yi1, Minhui Xu1,†()   

  1. 1. Department of Neurosurgery, Third Affiliated Hospital of the Army Medical University, Chongqing 400042, China
  • Received:2018-03-26 Published:2018-08-01
  • Corresponding author: Minhui Xu
  • About author:
    Corresponding Author: Xu Minhui, Email:
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引用本文：

马健行, 吴鹏飞, 杨伟, 廖茂君, 易良, 许民辉. 巨噬细胞浸润在低级别胶质瘤预后预测中的研究[J]. 中华细胞与干细胞杂志(电子版), 2018, 08(04): 204-211.

Jianxing Ma, Pengfei Wu, Wei Yang, Maojun Liao, Liang Yi, Minhui Xu. Macrophages infiltration in low grade glioma and its value in prognosis prediction[J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2018, 08(04): 204-211.

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-Whitney U?=?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-Whitney U?=?15?841，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?=?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-Whitney U?=?35，P < 0.01；Mann-Whitney U?=?20，P < 0.01）。IDH?1/2-?wt LGG较IDH?1/2-mu LGG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，CD163highIDH-?wt LGG患者的预后较CD163lowIDH-wt LGG患者差（P = 0.01），IL-10highIDH-mu LGG患者预后较IL-?10lowIDH-?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。

关键词: 胶质瘤, 肿瘤相关巨噬细胞, 异柠檬酸脱氢酶
Objective

To detect the infiltration degree and functional state of tumor-associated 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 CD163high patients was lower than the CD163low patients (P = 0.01), and the overall survival rate of the IL-10high patients was lower than IL-10low 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

Key words: Glioma, Tumor-associated macrophages, Isocitrate dehydrogenase
表1 Mann-Whitney U检验IDH1/2-wt和IDH1/2-mu LGG中巨噬细胞和TAM标志物表达
? CD68 CD11b IBA1 CD163 CD204
Mann-Whitney U 19425 15836 17758 18112 12676
Z值 -2.537 -5.053 -3.706 -3.457 -7.268
P值 0.011 0.0002 < 0.0001 0.0005 < 0.0001
图1 巨噬细胞和TAM标记物在IDH1/2-wt LGG和IDH1/2-mu LGG中的表达水平
表2 Mann-Whitney U检验免疫组化中CD68、CD163和CD204的表达
? CD68 CD163 CD204
Mann-Whitney U 51 35 20
Z值 -3.501 -4.008 -4.371
P值 0.0003 < 0.0001 < 0.0001
图2 光学显微镜下观察CD68、CD163和CD204在组织中的表达情况（DAB染色，×400）
图3 CD68、CD163和CD204在肿瘤组织切片中的表达
表3 Mann-Whitney U检验TAM趋化因子和免疫抑制因子表达
? CCL2 CCL5 POSTN VEGF-A Neurotensin IL-10 TGF-β
Mann-Whitney U值 15841 11326 8893 14433 15556 17334. 15459
Z值 -5.050 -8.214 -9.919 -6.036 -5.310 -4.003 -5.317
P值 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001
图4 TAM趋化因子、免疫抑制因子在IDH1/2-wt LGG和IDH1/2-mu LGG中的表达水平
图5 CD163和IL10表达水平对IDH-wt/mu LGG患者总生存期的影响
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