LOX-1+PMN-MDSC enhances immune suppression which promotes glioblastoma multiforme progression
LOX-1+PMN-MDSC enhances immune suppression which promotes glioblastoma multiforme progression
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DOI：
10.2147/cmar.s210545
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发表时间：
2019-01-01
影响因子：
3.3
通讯作者：
Li, Changqing
中科院分区：
文献类型：
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作者：
Chai, ErQing;Zhang, Lan;Li, Changqing
背景/目的：多形性胶质母细胞瘤（GBM）是成人中最常见的脑癌，患者预后相当差。免疫抑制性髓源性抑制细胞（MDSC）的积聚与多种癌症的临床结果呈负相关。最近的一项研究发现，凝集素样氧化低密度脂蛋白受体1（LOX - 1）可作为人多形核中性粒细胞（PMN）-MDSC的特异性标志物。因此，在此我们重点探讨LOX - 1⁺ PMN - MDSC在GBM进展中的作用。
方法：通过流式细胞术检测LOX - 1、干扰素 - γ、二氯二氢荧光素二乙酸酯（DCFDA）、CD15、CD4和CD8的表达水平。通过实时定量聚合酶链反应检测PMN中精氨酸酶1（ARG1）和诱导型一氧化氮合酶（iNOS）的表达水平。通过免疫荧光显微镜确定肿瘤组织中LOX - 1和CD15的表达水平。通过³H - 胸腺嘧啶核苷掺入法测定T细胞增殖。
结果：我们鉴定出一种PMN的促肿瘤亚群，其组成性表达LOX - 1并在GBM患者外周血中积聚。与LOX - 1⁻ PMN相比，LOX - 1⁺ PMN呈现出PMN - MDSC特征，DCFDA、ARG1和iNOS的表达显著增加，并以依赖ARG1/iNOS的方式抑制CD3⁺ T细胞增殖。此外，我们发现LOX - 1⁺ PMN与GBM患者的效应免疫细胞呈负相关，在GBM组织中积聚，并与早期复发和疾病进展密切相关。
结论：我们的研究表明，LOX - 1⁺ PMN - MDSC抑制T细胞增殖以增强免疫抑制，这可能在驱动GBM进展中起关键作用。
Background/aims: Patients with glioblastoma multiforme (GBM) that is the most common brain cancer in adults have a rather poor prognosis. The accumulation of immune suppressive myeloid-derived suppressor cell (MDSC) is negatively associated with clinical outcomes in various cancers. A recent study identified that lectin-type oxidized LDL receptor 1 (LOX-1) may serve as a specific marker of human polymorphonuclear neutrophil (PMN)-MDSC. Thus, herein we focused on exploring the role of LOX-1+ PMN-MDSC in GBM progression.Methods: LOX-1, IFN-gamma, dichlorodihydrofluorescein diacetate (DCFDA), CD15, CD4 and CD8 expression levels were examined by flow cytometry. ARG1 and iNOS expression levels in PMN were examined by quantitative real-time PCR. LOX-1 and CD15 expression levels in tumor tissue were determined by immunofluorescent microscopy. T cell proliferation was determined by 3H-thymidine incorporation.Results: We identified a protumorigenic subset of PMN, which constitutively expressed LOX-1 and accumulated in the peripheral blood of GBM patients. Compared to LOX-1-PMN, the LOX-1+ PMN exhibited a PMN MDSC profile, with a significant increase in the expression of DCFDA, ARG1 and iNOS, and the capacity of inhibiting the CD3+ T cell proliferation in a dependent-ARG1/iNOS way. Additionally, we found that LOX-1+ PMN negatively correlated with effector immune cells in GBM patients, accumulated in GBM tissues, and was related to early recurrence and disease progression tightly.Conclusion: Our study revealed that LOX-1+ PMN-MDSC inhibited the T cell proliferation to enhance immune suppression, which may play a key role in driving the GBM progression.