Dong Bo, Wu Chunli, Li Shi-Hao, Huang Lan, Zhang Chunyang, Wu Bin, Sheng Yinliang, Liu Yafei, Ye Guanchao, Qi Yu
Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Ann Transl Med. 2021 Sep;9(18):1465. doi: 10.21037/atm-21-4248.
Non-small cell lung cancer (NSCLC) is a common type of lung cancer with a poor prognosis. N6-methyladenosine (m6A) methylation, which is a reversible ribonucleic acid (RNA) modification, plays an important role in the occurrence and development of NSCLC. However, the potential effect of m6A methylation on immune infiltrates and prognosis remains unclear.
In this study, a weighted gene co-expression network analysis was used to screen out messenger RNAs (mRNAs) and non-coding RNAs (ncRNAs) that were co-expressed with m6A regulators. Additionally, 2 molecular subtypes (Clusters 1 and 2) were determined via consensus clustering. Subsequently, a prognostic risk model was constructed using both co-expressed mRNAs and ncRNAs. Based on the risk scores calculated by the prognostic model, the patients were divided into the high-risk group or low-risk group. Finally, the altered patterns of the tumor immune microenvironments (TIMEs) between the 2 stratification methods were thoroughly investigated, and a gene set enrichment analysis was conducted to further examine the potential mechanism.
Patients in Cluster 1 had lower immunoscores, higher programmed death-ligand 1 (PD-L1) expression, and shorter overall survival (OS) compared to patients in Cluster 2. A further investigation based on the prognostic model revealed that the PD-L1 expression levels of patients in the high-risk group were significantly upregulated, and the immunoscores were lower than those in the low-risk group. The immune cells with a high infiltration in Cluster 1 showed a significant positive correlation with the risk score; those with low infiltration showed a significant negative correlation. The hallmarks of the Myelocytomatosis viral oncogene (MYC) targets, the second Gap/Mitosis (G2/M) checkpoint, E2 transcription Factor (E2F) targets, glycolysis, deoxyribonucleic acid (DNA) repair, and unfolded protein response were significantly enriched in Cluster 1, the low-immunoscore group, and the high-risk group.
This study revealed that m6A methylation is closely related to the poor prognosis of NSCLC patients via interference with the TIME, which suggests that m6A may play a role in optimizing individualized immunotherapy management and improving prognosis.
非小细胞肺癌（NSCLC）是一种常见的肺癌类型，预后较差。N6-甲基腺苷（m6A）甲基化是一种可逆的核糖核酸（RNA）修饰，在NSCLC的发生和发展中起重要作用。然而，m6A甲基化对免疫浸润和预后的潜在影响仍不清楚。
在本研究中，使用加权基因共表达网络分析筛选出与m6A调节因子共表达的信使核糖核酸（mRNA）和非编码核糖核酸（ncRNA）。此外，通过一致性聚类确定了2种分子亚型（簇1和簇2）。随后，使用共表达的mRNA和ncRNA构建预后风险模型。根据预后模型计算的风险评分，将患者分为高风险组或低风险组。最后，深入研究了两种分层方法之间肿瘤免疫微环境（TIME）的改变模式，并进行基因集富集分析以进一步研究潜在机制。
与簇2中的患者相比，簇1中的患者免疫评分较低，程序性死亡配体1（PD-L1）表达较高，总生存期（OS）较短。基于预后模型的进一步研究表明，高风险组患者的PD-L1表达水平显著上调，免疫评分低于低风险组。簇1中高浸润的免疫细胞与风险评分呈显著正相关；低浸润的免疫细胞与风险评分呈显著负相关。髓细胞瘤病毒癌基因（MYC）靶点、第二个间隙/有丝分裂（G2/M）检查点、E2转录因子（E2F）靶点、糖酵解、脱氧核糖核酸（DNA）修复和未折叠蛋白反应的特征在簇1、低免疫评分组和高风险组中显著富集。
本研究表明，m6A甲基化通过干扰TIME与NSCLC患者的不良预后密切相关，这表明m6A可能在优化个体化免疫治疗管理和改善预后方面发挥作用。
