mA 调节剂介导的甲基化修饰模式及胃癌肿瘤微环境浸润特征。
mA regulator-mediated methylation modification patterns and tumor microenvironment infiltration characterization in gastric cancer.
机构信息
Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, China.
Medical School of Nantong University, Nantong, 226001, Jiangsu Province, China.
出版信息
Mol Cancer. 2020 Mar 12;19(1):53. doi: 10.1186/s12943-020-01170-0.
BACKGROUND
The epigenetic regulation of immune response has been demonstrated in recent studies. Nonetheless, potential roles of RNA N6-methyladenosine (mA) modification in tumor microenvironment (TME) cell infiltration remain unknown.
METHODS
We comprehensively evaluated the mA modification patterns of 1938 gastric cancer samples based on 21 mA regulators, and systematically correlated these modification patterns with TME cell-infiltrating characteristics. The m6Ascore was constructed to quantify mA modification patterns of individual tumors using principal component analysis algorithms.
RESULTS
Three distinct mA modification patterns were determined. The TME cell-infiltrating characteristics under these three patterns were highly consistent with the three immune phenotypes of tumors including immune-excluded, immune-inflamed and immune-desert phenotypes. We demonstrated the evaluation of mA modification patterns within individual tumors could predict stages of tumor inflammation, subtypes, TME stromal activity, genetic variation, and patient prognosis. Low m6Ascore, characterized by increased mutation burden and activation of immunity, indicated an inflamed TME phenotype, with 69.4% 5-year survival. Activation of stroma and lack of effective immune infiltration were observed in the high m6Ascore subtype, indicating a non-inflamed and immune-exclusion TME phenotype, with poorer survival. Low m6Ascore was also linked to increased neoantigen load and enhanced response to anti-PD-1/L1 immunotherapy. Two immunotherapy cohorts confirmed patients with lower m6Ascore demonstrated significant therapeutic advantages and clinical benefits.
CONCLUSIONS
This work revealed the mA modification played a nonnegligible role in formation of TME diversity and complexity. Evaluating the mA modification pattern of individual tumor will contribute to enhancing our cognition of TME infiltration characterization and guiding more effective immunotherapy strategies.
背景
最近的研究表明，免疫反应的表观遗传调控。然而，RNA N6-甲基腺苷（mA）修饰在肿瘤微环境（TME）细胞浸润中的潜在作用尚不清楚。
方法
我们基于 21 个 mA 调节剂，全面评估了 1938 个胃癌样本中的 mA 修饰模式，并系统地将这些修饰模式与 TME 细胞浸润特征相关联。使用主成分分析算法构建 m6Ascore 来量化个体肿瘤的 mA 修饰模式。
结果
确定了三种不同的 mA 修饰模式。这三种模式下的 TME 细胞浸润特征与肿瘤的三种免疫表型高度一致，包括免疫排斥、免疫炎症和免疫荒漠表型。我们证明了评估个体肿瘤内 mA 修饰模式可以预测肿瘤炎症阶段、亚型、TME 基质活性、遗传变异和患者预后。低 m6Ascore 特征为突变负担增加和免疫激活，表明 TME 表型呈炎症状态，5 年生存率为 69.4%。高 m6Ascore 亚型观察到基质激活和有效免疫浸润缺乏，表明 TME 表型呈非炎症和免疫排斥状态，生存率较差。低 m6Ascore 还与新抗原负荷增加和对抗 PD-1/L1 免疫治疗的反应增强相关。两个免疫治疗队列证实，m6Ascore 较低的患者表现出显著的治疗优势和临床获益。
结论
这项工作揭示了 mA 修饰在形成 TME 多样性和复杂性方面发挥了不可忽视的作用。评估个体肿瘤的 mA 修饰模式将有助于增强我们对 TME 浸润特征的认识，并指导更有效的免疫治疗策略。
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