Department of Gastrointestinal Surgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China.
Fujian Provincial Key Laboratory of Precision Medicine for Cancer, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China.
Sci Rep. 2023 Jul 24;13(1):11950. doi: 10.1038/s41598-023-37300-z.
The RNA 5-methylcytosine (m5C) modification has been demonstrated to be an important epigenetic regulator and to impact colorectal cancer (CRC) progression. However, the potential roles of m5C modification in immune cell infiltration in the CRC tumor microenvironment (TME) remain unknown. The m5C modification phenotypes were comprehensively evaluated based on 14 m5C regulators in a meta-CRC cohort of 1792 patients and systematically correlated with the m5C modification phenotypes, immune cell infiltration characteristics and known biological processes. The m5Cscore model was constructed by principal component analysis (PCA) algorithms to quantify the m5C modification phenotypes of individual CRC samples and was used to predict the immunotherapy response. We identified three m5C modification phenotypes associated with distinct clinical outcomes and biological processes among the 1792 meta-CRC patients. Three phenotypes with a highly consistent TME landscape and characteristics were revealed: immune excluded, immune desert and immune inflammation. The meta-CRC patients were divided into high and low m5Cscore subgroups based on the m5Cscore. The m5Cscore was confirmed to have a negative correlation with infiltrating immune cells and PD-L1 expression and a positive correlation with tumor mutation burden (TMB), mutation rate and microsatellite instability (MSI) score. Moreover, patients in the low m5Cscore group had better immunotherapy responses and significant durable survival benefits in independent anti-PD-1/L1 immunotherapy cohorts for the immune checkpoint inhibitor (ICI) therapeutic strategy. This study revealed that m5C modification plays a crucial role in TME composition and complexity. Comprehensive evaluation of the m5C modification phenotypes of individual patients will enhance our understanding of TME characteristics and promote the application of more appropriate and personalized treatment strategies.
RNA 5-甲基胞嘧啶（m5C）修饰已被证明是一种重要的表观遗传调节剂，可影响结直肠癌（CRC）的进展。然而，m5C 修饰在 CRC 肿瘤微环境（TME）中免疫细胞浸润中的潜在作用仍不清楚。在 1792 例 meta-CRC 患者的队列中，全面评估了 14 个 m5C 调节剂的 m5C 修饰表型，并与 m5C 修饰表型、免疫细胞浸润特征和已知的生物学过程进行了系统相关性分析。通过主成分分析（PCA）算法构建 m5Cscore 模型，以量化个体 CRC 样本的 m5C 修饰表型，并用于预测免疫治疗反应。我们在 1792 例 meta-CRC 患者中鉴定了三种与不同临床结局和生物学过程相关的 m5C 修饰表型。揭示了三种具有高度一致的 TME 景观和特征的表型：免疫排斥、免疫荒漠和免疫炎症。根据 m5Cscore 将 meta-CRC 患者分为高 m5Cscore 和低 m5Cscore 亚组。m5Cscore 与浸润免疫细胞和 PD-L1 表达呈负相关，与肿瘤突变负荷（TMB）、突变率和微卫星不稳定性（MSI）评分呈正相关。此外，在独立的抗 PD-1/L1 免疫治疗队列中，低 m5Cscore 组患者对免疫检查点抑制剂（ICI）治疗策略的免疫治疗反应更好，具有显著的持久生存获益。这项研究表明，m5C 修饰在 TME 组成和复杂性中发挥着关键作用。对个体患者 m5C 修饰表型的全面评估将增强我们对 TME 特征的理解，并促进更合适和个性化治疗策略的应用。
