Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Graduate School, Zunyi Medical University, Zunyi, China.
Front Immunol. 2021 May 12;12:669750. doi: 10.3389/fimmu.2021.669750. eCollection 2021.
Esophageal squamous cell carcinoma (ESCC) is one of the most common cancer types and represents a threat to global public health. N6-Methyladenosine (m6A) methylation plays a key role in the occurrence and development of many tumors, but there are still few studies investigating ESCC. This study attempts to construct a prognostic signature of ESCC based on m6A RNA methylation regulators and to explore the potential association of these regulators with the tumor immune microenvironment (TIME).
The transcriptome sequencing data and clinical information of 20 m6A RNA methylation regulators in 453 patients with ESCC (The Cancer Genome Atlas [TCGA] cohort, n = 95; Gene Expression Omnibus [GEO] cohort, n = 358) were obtained. The differing expression levels of m6A regulators between ESCC and normal tissue were evaluated. Based on the expression of these regulators, consensus clustering was performed to investigate different ESCC clusters. PD-L1 expression, immune score, immune cell infiltration and potential mechanisms among different clusters were examined. LASSO Cox regression analysis was utilized to obtain a prognostic signature based on m6A RNA methylation modulators. The relationship between the risk score based on the prognostic signature and the TIME of ESCC patients was studied in detail.
Six m6A regulators (METTL3, WTAP, IGF2BP3, YTHDF1, HNRNPA2B1 and HNRNPC) were observed to be significantly highly expressed in ESCC tissues. Two molecular subtypes (clusters 1/2) were determined by consensus clustering of 20 m6A modulators. The expression level of PD-L1 in ESCC tissues increased significantly and was significantly negatively correlated with the expression levels of YTHDF2, METL14 and KIAA1429. The immune score, CD8 T cells, resting mast cells, and regulatory T cells (Tregs) in cluster 2 were significantly increased. Gene set enrichment analysis (GSEA) shows that this cluster involves multiple hallmark pathways. We constructed a five-gene prognostic signature based on m6A RNA methylation, and the risk score based on the prognostic signature was determined to be an independent prognostic indicator of ESCC. More importantly, the prognostic value of the prognostic signature was verified using another independent cohort. m6A regulators are related to TIME, and their copy-number alterations will dynamically affect the number of tumor-infiltrating immune cells.
Our study established a strong prognostic signature based on m6A RNA methylation regulators; this signature was able to accurately predict the prognosis of ESCC patients. The m6A methylation regulator may be a key mediator of PD-L1 expression and immune cell infiltration and may strongly affect the TIME of ESCC.
食管鳞状细胞癌（ESCC）是最常见的癌症类型之一，对全球公共健康构成威胁。N6-甲基腺苷（m6A）甲基化在许多肿瘤的发生和发展中起着关键作用，但目前关于 ESCC 的研究仍然较少。本研究试图基于 m6A RNA 甲基化调节剂构建 ESCC 的预后特征，并探讨这些调节剂与肿瘤免疫微环境（TIME）的潜在关联。
获取 20 个 m6A RNA 甲基化调节剂在 453 例 ESCC 患者（TCGA 队列，n=95；GEO 队列，n=358）中的转录组测序数据和临床信息。评估 m6A 调节剂在 ESCC 与正常组织之间的差异表达水平。基于这些调节剂的表达，进行共识聚类以研究不同的 ESCC 聚类。检查不同聚类中 PD-L1 表达、免疫评分、免疫细胞浸润和潜在机制。利用 LASSO Cox 回归分析基于 m6A RNA 甲基化调节剂获得预后特征。详细研究基于预后特征的风险评分与 ESCC 患者 TIME 的关系。
观察到 6 个 m6A 调节剂（METTL3、WTAP、IGF2BP3、YTHDF1、HNRNPA2B1 和 HNRNPC）在 ESCC 组织中显著高表达。通过 20 个 m6A 调节剂的共识聚类确定了两个分子亚型（簇 1/2）。ESCC 组织中 PD-L1 的表达水平显著升高，与 YTHDF2、METL14 和 KIAA1429 的表达水平呈显著负相关。簇 2 中的免疫评分、CD8 T 细胞、静止肥大细胞和调节性 T 细胞（Tregs）显著增加。基因集富集分析（GSEA）表明该聚类涉及多个标志性途径。我们基于 m6A RNA 甲基化构建了一个由五个基因组成的预后特征，基于预后特征的风险评分被确定为 ESCC 的独立预后指标。更重要的是，使用另一个独立队列验证了预后特征的预后价值。m6A 调节剂与 TIME 相关，其拷贝数改变将动态影响肿瘤浸润免疫细胞的数量。
本研究建立了基于 m6A RNA 甲基化调节剂的强大预后特征；该特征能够准确预测 ESCC 患者的预后。m6A 甲基化调节剂可能是 PD-L1 表达和免疫细胞浸润的关键介质，并可能强烈影响 ESCC 的 TIME。
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