HHLA2 is a novel prognostic predictor and potential therapeutic target in malignant glioma
HHLA2 is a novel prognostic predictor and potential therapeutic target in malignant glioma
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HHLA2 是恶性胶质瘤的新型预后预测因子和潜在治疗靶点
DOI：
10.3892/or.2019.7343
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发表时间：
2019-12-01
期刊：
影响因子：
4.2
通讯作者：
Chen, Qianxue
中科院分区：
文献类型：
--
作者：
Qi, Yangzhi;Deng, Gang;Chen, Qianxue
神经胶质瘤是中枢神经系统最常见和最具侵袭性的肿瘤类型，并且与不良预后相关。到目前为止，新出现的免疫疗法已经显著改善了各种癌症患者的预后。人内源性逆转录病毒-H长末端重复序列相关蛋白2（HHLA 2）是一种新发现的免疫检查点分子，已被证明是一种新的治疗靶点。因此，本研究旨在探讨HHLA 2在胶质瘤中的临床预后价值及其机制作用。对来自癌症基因组图谱的数据集进行了系统回顾。对669例患者的RNA-seq数据进行分析，并通过GO和途径富集分析预测HHLA 2的生物学功能。HHLA 2的免疫组织化学标记图像从人类蛋白质图谱中获得。采用xCell对胶质瘤肿瘤浸润免疫细胞模型进行综合分析。采用考克斯比例风险回归模型预测胶质瘤患者的预后。结果显示，高级别胶质瘤、异柠檬酸脱氢酶野生型、1 p/19 q无缺失、端粒酶逆转录酶启动子突变的胶质瘤中HHLA 2表达水平明显降低。受试者操作特征分析显示HHLA 2是神经亚型的预测因子。肿瘤浸润免疫细胞模型表明，HLA 2与肿瘤相关的巨噬细胞呈负相关。GO分析和途径富集分析显示，HHLA 2相关基因在功能上参与抑制肿瘤相关过程。HHLA 2与某些基因显著负相关，包括白细胞介素-10、转化生长因子-β、血管内皮生长因子和δ样经典Notch配体4，以及其他免疫检查点分子，包括程序性细胞死亡1、淋巴细胞活化3和CD 276。生存分析提示HHLA 2高表达者预后良好。总之，本研究揭示了HHLA 2的上调与胶质瘤患者的良好预后显著相关。以HLA 2为靶点的免疫刺激剂有望成为治疗脑胶质瘤的一种有价值的方法。
Glioma is the most common and aggressive tumor type of the central nervous system and is associated with poor prognosis. To date, novel emerging immunotherapies have significantly improved outcomes for patients with various cancer types. Human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2), a newly discovered immune checkpoint molecule, has demonstrated its potential as a novel therapeutic target. Therefore, the present study aimed to investigate the clinical prognostic value of HHLA2 in gliomas and its mechanistic role. A systematic review of datasets from The Cancer Genome Atlas was performed. The RNA-seq data of a total of 669 cases were analyzed and the biological function of HHLA2 was predicted by Gene Ontology (GO) and pathway enrichment analysis. Immunohistochemistry labelling images for HHLA2 was obtained from the Human Protein Atlas. xCell was used to comprehensively analyze the model of tumor-infiltrating immune cell in glioma. The Cox proportional hazards regression model was used to predict outcomes for glioma patients. The results revealed that the expression levels of HHLA2 were significantly lower in high-grade glioma, as well as glioma with wild-type isocitrate dehydrogenase, no deletion of 1p/19q and telomerase reverse transcriptase promoter mutation. Receiver operating characteristic analysis revealed that HHLA2 was a predictor of the neural subtype. The tumor-infiltrating immune cell model indicated that HHLA2 was negatively associated with tumor-associated macrophages. GO analysis and pathway enrichment analysis revealed that HHLA2-associated genes were functionally involved in inhibition of neoplasia-associated processes. HHLA2 was significantly negatively correlated with certain genes, including interleukin-10, transforming growth factor-beta, vascular endothelial growth factor and delta-like canonical Notch ligand 4, and other immune checkpoint molecules, including programmed cell death 1, lymphocyte activating 3 and CD276. Survival analysis indicated that high expression of HHLA2 predicted a favorable prognosis. In conclusion, the present study revealed that upregulation of HHLA2 is significantly associated with a favorable outcome for patients with glioma. Targeting HHLA2 as an immune stimulator may become a valuable approach for the treatment of glioma in clinical practice.