Comprehensive Analysis of the PD-L1 and Immune Infiltrates of m6A RNA Methylation Regulators in Head and Neck Squamous Cell Carcinoma
Comprehensive Analysis of the PD-L1 and Immune Infiltrates of m6A RNA Methylation Regulators in Head and Neck Squamous Cell Carcinoma
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DOI：
10.1016/j.omtn.2020.06.001
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发表时间：
2020-09-04
影响因子：
8.8
通讯作者：
Huang, Ping
中科院分区：
文献类型：
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作者：
Yi, Lilan;Wu, Guowu;Huang, Ping
由于大多数研究都集中在肿瘤的内在致癌途径，N6-甲基腺苷（m（6）A）甲基化在肿瘤免疫微环境（TIME）中的潜在作用仍然难以捉摸。在此，我们系统地探讨了769例头颈部鳞状细胞癌（HNSCC;癌症基因组图谱[TCGA]队列，n = 499; GSE 65858队列，n = 270）中主要m（6）A调节因子与PD-L1和免疫浸润的相关性。PD-L1表达与m（6）A调节因子明显相关。通过对15 m（6）A调节子的一致聚类，鉴定了两种分子亚型（cluster 1/2）。簇2优先与良好的预后、上调的PD-L1表达、较高的免疫评分和明显的免疫细胞浸润相关。G2 M检查点、mTORC 1信号传导和PI 3 K/ AKT/mTOR信号传导的标志在簇1中显著富集。使用7个m（6）A调节相关的标志构建预后风险评分，这些标志代表HNSCC的独立预后因素。低风险评分的患者比高风险评分的患者表现出更高的免疫评分和上调的PD-L1表达。一致地，m（6）A调节剂在外部GSE 65858队列中对免疫调节和存活显示出相同的影响。进一步的分析显示，m（6）A调节子为基础的信号与TIME有关，它们的拷贝数变化动态地影响肿瘤浸润免疫细胞的丰度。总之，本研究阐明了m（6）A甲基化在HNSCC的TIME中的重要作用.提出的基于m（6）A调节剂的签名可能作为HNSCC中TIME的关键介质，代表了改善免疫功效的有希望的治疗靶点。
Because most studies have focused on the intrinsic carcinogenic pathways of tumors, the underlying role of N6-methyladenosine (m(6)A) methylation in tumor immune microenvironment (TIME) remains elusive. Herein, we systematically explored the correlations of prominent m(6)A regulators with PD-L1 and immune infiltrates in 769 head and neck squamous cell carcinomas (HNSCCs; The Cancer Genome Atlas [TCGA] cohort, n = 499; GSE65858 cohort, n = 270). The PD-L1 expression evidently associated with m(6)A regulators. Two molecular subtypes (cluster1/2) were identified by consensus clustering for 15 m(6)A regulators. The cluster2 preferentially associated with favorable prognosis, upregulated PD-L1 expression, higher immunoscore, and distinct immune cell infiltration. The hallmarks of G2M checkpoint, mTORC1 signaling, and PI3K/ AKT/mTOR signaling were remarkably enriched in the cluster1. A prognostic risk score was constructed using seven m(6)A regulator-associated signatures that represented an independent prognosis factor for HNSCC. Patients with low-risk score exhibited higher immunoscore and upregulated PD-L1 expression than patients with high-risk score. Consistently, m(6)A regulators showed the same influence on immune modulation and survival in external GSE65858 cohort. Further analysis revealed that m(6)A regulator-based signatures were implicated in TIME and their copy-number alterations dynamically affected the abundance of tumor-infiltrating immune cells. Collectively, our study elucidated the important role of m(6)A methylation in TIME of HNSCC. The proposed m(6)A regulator-based signatures might serve as crucial mediators of TIME in HNSCC, representing promising therapeutic targets in improving immunotherapeutic efficacy.