Chen Quan, Wan Weijun, Zhao Qing, Li Juan, Xiong Yanli, Yuan Yuchuan, Tang Lu, Wu Xiaofeng, Xing Wei, Guo Wei, Lu Di, Ao Luoquan, Xu Xiang, Ao Xiang
State Key Laboratory of Trauma and Chemical Poisoning, Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, China.
Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Science and Technology Achievement Incubation Center, Kunming Medical University, Kunming, China.
Front Immunol. 2024 Dec 10;15:1514497. doi: 10.3389/fimmu.2024.1514497. eCollection 2024.
To determine the role of N-methyladenosine (mA) modification in the tumor immune microenvironment (TIME), as well as their association with lung adenocarcinoma (LUAD).
Consensus clustering was performed to identify the subgroups with distinct immune or mA modification patterns using profiles from TCGA. A risk score model was constructed using least absolute shrinkage and selection operator regression and validated in two independent cohorts and LUAD tissue microarrays. For experimental validation, the regulation of METTL3/mA axis in the expression of candidate genes by RIP-qPCR assay in A549 and H460 cell lines. Co-culture experiments with human T cells were performed to evaluate the impact of METTL3 on the enhancement of anti-tumor immunity through experiments.
We identified 282 mA regulator genes and 955 immune-related genes, selecting seven key genes (SFTPC, CYP24A1, KRT6A, PTTG1, S100P, FAM83A, and ANLN) to develop a risk score model using Lasso regression. High-risk patients, determined by this model, exhibited poorer prognosis, increased immune infiltration, higher tumor mutational burden, more neoantigens, and elevated PD-L1 expression. These findings were validated by two independent databases and LUAD tissue microarrays. METTL3 was found to impact the mRNA expression of these genes, with METTL3 deficiency abolishing these interactions. Inhibition of METTL3 enhanced anti-tumor immunity, T cell activation, exhaustion, and infiltration .
This risk score system shows promise for prognostic prediction and the development of personalized treatment strategies for LUAD patients.
确定N-甲基腺苷（mA）修饰在肿瘤免疫微环境（TIME）中的作用及其与肺腺癌（LUAD）的关联。
使用来自TCGA的图谱进行一致性聚类，以识别具有不同免疫或mA修饰模式的亚组。使用最小绝对收缩和选择算子回归构建风险评分模型，并在两个独立队列和LUAD组织微阵列中进行验证。为了进行实验验证，通过A549和H460细胞系中的RIP-qPCR分析，研究METTL3/mA轴对候选基因表达的调控。通过与人类T细胞共培养实验，评估METTL3对增强抗肿瘤免疫的影响。
我们鉴定出282个mA调节基因和955个免疫相关基因，选择七个关键基因（SFTPC、CYP24A1、KRT6A、PTTG1、S100P、FAM83A和ANLN），使用套索回归开发风险评分模型。由该模型确定的高风险患者预后较差，免疫浸润增加，肿瘤突变负担更高，新抗原更多，PD-L1表达升高。这些发现通过两个独立数据库和LUAD组织微阵列得到验证。发现METTL3影响这些基因的mRNA表达，METTL3缺陷消除了这些相互作用。抑制METTL3可增强抗肿瘤免疫、T细胞活化、耗竭和浸润。
该风险评分系统在预测LUAD患者预后及制定个性化治疗策略方面显示出前景。
