利用新型m6A调节因子介导的甲基化修饰模式在不同肿瘤微环境特征中识别和预测胶质瘤的预后与进展、T细胞功能障碍以及对ICI免疫疗法的临床反应。
Use of Novel m6A Regulator-mediated Methylation Modification Patterns in Distinct Tumor Microenvironment Profiles to Identify and Predict Glioma Prognosis and Progression, T-cell Dysfunction, and Clinical Response to ICI Immunotherapy.
作者信息
Zhao Binghao, Xiang Zhongtian, Wu Bo, Zhang Xiang, Feng Nan, Wei Yiping, Zhang Wenxiong
机构信息
Department of Thoracic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China.
Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R, China.
出版信息
Curr Pharm Des. 2023;29(1):60-78. doi: 10.2174/1381612829666221207112438.
BACKGROUND
The specific functions of RNA N6-methyladenosine (m6A) modifications in the glioma tumor microenvironment (TME) and glioma patient prognosis and treatment have not been determined to date.
OBJECTIVE
The objective of the study was to determine the role of m6A modifications in glioma TME.
METHODS
Nonnegative matrix factorization (NMF) methods were used to determine m6A clusters and m6A gene signatures based on 21 genes relating to m6A modifications. TME characteristics for each m6A cluster and m6A gene signature were quantified by established m6A score. The utility of m6A score was validated in immunotherapy and other antiangiogenic treatment cohorts.
RESULTS
Three m6A clusters were identified among 3,395 glioma samples, and they were linked to different biological activities and clinical outcomes. The m6A clusters were highly consistent with immune profiles known as immune-inflamed, immune-excluded, and immune-desert phenotypes. Clusters within individual tumors could predict glioma inflammation, molecular subtypes, TME stromal activity, genetic variation, alternative splicing, and prognosis. As for the m6A score and m6A gene signature, patients with low m6A scores exhibited an increased tumor mutation burden, immune activity, neoantigen load, and prolonged survival. A low m6A score indicated the potential for a low level of T-cell dysfunction, a considerably better treatment response, and durable clinical benefits from immunotherapy, bevacizumab and regorafenib.
CONCLUSION
Glioma m6A clusters and gene signatures have distinctive TME features. The m6A gene signature may guide prognostic assessments and promote the use of effective strategies.
背景
RNA N6-甲基腺苷（m6A）修饰在胶质瘤肿瘤微环境（TME）以及胶质瘤患者预后和治疗中的具体功能至今尚未明确。
目的
本研究旨在确定m6A修饰在胶质瘤TME中的作用。
方法
基于与m6A修饰相关的21个基因，采用非负矩阵分解（NMF）方法确定m6A簇和m6A基因特征。通过既定的m6A评分对每个m6A簇和m6A基因特征的TME特征进行量化。在免疫治疗和其他抗血管生成治疗队列中验证了m6A评分的效用。
结果
在3395例胶质瘤样本中鉴定出三个m6A簇，它们与不同的生物学活性和临床结果相关。m6A簇与已知的免疫炎症、免疫排除和免疫沙漠表型的免疫谱高度一致。单个肿瘤内的簇可预测胶质瘤炎症、分子亚型、TME基质活性、基因变异、可变剪接和预后。至于m6A评分和m6A基因特征，m6A评分低的患者表现出肿瘤突变负担增加、免疫活性增强、新抗原负荷增加和生存期延长。低m6A评分表明T细胞功能障碍水平较低、治疗反应明显更好以及从免疫治疗、贝伐单抗和瑞戈非尼中获得持久临床益处的可能性。
结论
胶质瘤m6A簇和基因特征具有独特的TME特征。m6A基因特征可指导预后评估并促进有效策略的应用。
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