Department of Radiotherapy, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, China.
Department of Radiotherapy, Graduate School of Dalian Medical University, Dalian, China.
J Cancer Res Clin Oncol. 2022 Oct;148(10):2803-2814. doi: 10.1007/s00432-022-04032-y. Epub 2022 May 20.
The m6A methylation modification is one of the most common mRNA modifications, and involved in a variety of biological processes, such as cell death, cancer stem cell formation and tumorigenesis. Increasing evidences have demonstrated that the expression patterns of m6A regulators are significantly correlated with PD-L1 level some solid tumors, but few study has explored the function of m6A regulators in the immune microenvironment and prognosis in non-small cell lung cancer (NSCLC).
Survival analysis was independently conducted for 20 m6A regulators to explore their prognostic value in NSCLC, and then the prognostic risk model based on m6A regulator expression profiles is built to stratify NSCLC patients. Also, the correlation analysis between immune infiltrating cells and m6A regulators is used to reveal the impact of m6A on immune microenvironment of NSCLC. Furthermore, to explore the function of m6A as biomarker of anit-PD-L1 therapeutic effect, we explored the associations of tumor mutation burden (TMB) and PD-L1 levels to 20 m6A regulator expression patterns in NSCLC.
First, the expressions of 20 m6A regulators in NSCLC tissues were significantly increased compared to normal tissues. Survival analysis revealed that three genes, METTL3, HNRNPC and VIRMA, were markedly correlated to the prognosis of NSCLC patients. In particular, cox regression analysis verified that METTL3 could be used as an independent prognostic factor to predict the survival rate of NSCLC patients. Second, the risk prognostic model built on seven m6A regulators can effectively stratify NSCLC patients, and the low-risk subgroup had better prognosis compared to high-risk group. Finally, a few m6A regulators showed significant associations with immune microenvironment, as well as TMB and PD-L1 level, suggesting that the m6A RNA methylation is indicative of therapeutic effect of anti-PD-L1 treatment.
Our study identified some m6A regulatory factors as independent risk factors for the prognosis of NSCLC, and the expression patterns of m6A regulators are also correlated to the immune infiltration, as well as TMB and PD-L1 level in NSCLC. The m6A regulators could be used as biomarkers indicative of immunotherapy to NSCLC patients.
m6A 甲基化修饰是最常见的 mRNA 修饰之一，参与多种生物学过程，如细胞死亡、癌症干细胞形成和肿瘤发生。越来越多的证据表明，m6A 调节因子的表达模式与一些实体瘤的 PD-L1 水平显著相关，但很少有研究探讨 m6A 调节因子在非小细胞肺癌（NSCLC）中的免疫微环境和预后中的功能。
对 20 个 m6A 调节剂进行生存分析，以探讨其在 NSCLC 中的预后价值，然后构建基于 m6A 调节剂表达谱的预后风险模型，对 NSCLC 患者进行分层。此外，还对免疫浸润细胞与 m6A 调节剂的相关性进行分析，以揭示 m6A 对 NSCLC 免疫微环境的影响。此外，为了探讨 m6A 作为抗 PD-L1 治疗效果生物标志物的功能，我们探讨了肿瘤突变负担（TMB）和 PD-L1 水平与 NSCLC 中 20 个 m6A 调节剂表达模式的相关性。
首先，与正常组织相比，NSCLC 组织中 20 个 m6A 调节剂的表达明显增加。生存分析显示，METTL3、HNRNPC 和 VIRMA 这三个基因与 NSCLC 患者的预后显著相关。特别是 Cox 回归分析验证了 METTL3 可以作为独立的预后因素预测 NSCLC 患者的生存率。其次，基于七个 m6A 调节剂构建的风险预后模型可以有效地对 NSCLC 患者进行分层，低风险亚组的预后明显优于高风险组。最后，一些 m6A 调节剂与免疫微环境以及 TMB 和 PD-L1 水平有显著相关性，提示 m6A RNA 甲基化预示着抗 PD-L1 治疗的疗效。
本研究鉴定了一些 m6A 调节因子作为 NSCLC 预后的独立危险因素，m6A 调节因子的表达模式也与 NSCLC 中的免疫浸润以及 TMB 和 PD-L1 水平相关。m6A 调节剂可以作为 NSCLC 患者免疫治疗的生物标志物。
