Growing evidences indicate DNA methylation plays a crucial regulatory role in inflammation, innate immunity, and immunotherapy. However, the overall landscape of various DNA methylation regulatory genes and their relationship with the infiltration of immune cells into the tumor microenvironment (TME) as well as the response to immunotherapy in gliomas is still not clear. Therefore, we comprehensively analyzed the correlation between DNA methylation regulator patterns, infiltration of immune cell-types, and tumor immune response status in gather glioma cohorts. Furthermore, we calculated the DNA methylation score (DMS) for individual glioma samples, then evaluated the relationship between DMS, clinicopathological characteristics, and overall survival (OS) in patients with gliomas. Our results showed three distinct DNA methylation regulator patterns among the glioma patients which correlated with three distinct tumor immune response phenotypes, namely, immune-inflamed, immune-excluded, and immune desert. We then calculated DMS for individual glioma samples based on the expression of DNA methylation-related gene clusters. Furthermore, DMS, tumor mutation burden (TMB), programmed death 1 (PD-1) expression, immune cell infiltration status in the TME, and Tumor Immune Dysfunction and Exclusion (TIDE) scores were associated with survival outcomes and clinical responses to immune checkpoint blockade therapy. We also validated the predictive value of DMS in two independent immunotherapy cohorts. In conclusion, our results demonstrated that three DNA methylation regulator patterns that correlated with three tumor immune response phenotypes. Moreover, we demonstrated that DMS was an independent predictive biomarker that correlated with survival outcomes of glioma patients and their responses to immunotherapy therapeutic regimens.

中文翻译：

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神经胶质瘤中 DNA 甲基化调节剂介导的修饰模式和肿瘤微环境特征

越来越多的证据表明 DNA 甲基化在炎症、先天免疫和免疫治疗中起着至关重要的调节作用。然而，各种 DNA 甲基化调控基因的总体情况及其与免疫细胞浸润到肿瘤微环境 (TME) 的关系以及胶质瘤对免疫治疗的反应仍不清楚。因此，我们综合分析了胶质瘤队列中 DNA 甲基化调节模式、免疫细胞类型浸润和肿瘤免疫反应状态之间的相关性。此外，我们计算了单个神经胶质瘤样本的 DNA 甲基化评分 (DMS)，然后评估了神经胶质瘤患者的 DMS、临床病理学特征和总生存期 (OS) 之间的关系。我们的研究结果表明，神经胶质瘤患者中存在三种不同的 DNA 甲基化调节模式，这些模式与三种不同的肿瘤免疫反应表型相关，即免疫炎症、免疫排除和免疫沙漠。然后，我们根据 DNA 甲基化相关基因簇的表达计算了单个神经胶质瘤样本的 DMS。此外，DMS、肿瘤突变负荷 (TMB)、程序性死亡 1 (PD-1) 表达、TME 中的免疫细胞浸润状态以及肿瘤免疫功能障碍和排除 (TIDE) 评分与生存结果和对免疫检查点的临床反应相关阻断疗法。我们还在两个独立的免疫治疗队列中验证了 DMS 的预测价值。综上所述，我们的结果表明，三种 DNA 甲基化调节模式与三种肿瘤免疫反应表型相关。此外，我们证明 DMS 是一种独立的预测性生物标志物，与神经胶质瘤患者的生存结果及其对免疫治疗方案的反应相关。