Zhang Shichao, Xiong Yu, Zheng Chaochao, Long Jinhua, Zhou Houming, Zeng Zhu, Ouyang Yan, Tang Fuzhou
Key Laboratory of Infectious Immune and Antibody Engineering in Guizhou Province, School of Biology and Engineering, Guizhou Medical University, Guiyang, China.
Immune Cells and Antibody Engineering Research Center of Guizhou Province, School of Biology and Engineering, Guizhou Medical University, Guiyang, China.
Front Cell Dev Biol. 2022 Jan 26;10:821678. doi: 10.3389/fcell.2022.821678. eCollection 2022.
The "writers" of four types of adenosine (A)-related RNA modifications (N6-methyladenosine, N1-methyladenosine, alternative polyadenylation, as well as A-to-inosine RNA editing) are closely related to the tumorigenesis and progression of many cancer types, including skin cutaneous melanoma (SKCM). However, the potential roles of the crosstalk between these RNA modification "writers" in the tumor microenvironment (TME) remain unclear. The RNA modification patterns were identified using an unsupervised clustering method. Subsequently, based on differentially expressed genes responsible for the aforementioned RNA modification patterns, an RNA modification "writer" scoring model (W_Score) was constructed to quantify the RNA modification-associated subtypes in individual patients. Moreover, a correlation analysis for W_Score and the TME characteristics, clinical features, molecular subtypes, drug sensitivities, immune responses, and prognosis was performed. We identified three RNA modification patterns, corresponding to distinct tumor immune microenvironment characteristics and survival outcomes. Based on the W_Score score, which was extracted from the RNA modification-related signature genes, patients with SKCM were divided into high- and low-W_Score groups. The low-W_Score group was characterized by better survival outcomes and strengthened immunocyte infiltration. Further analysis showed that the low-W_Score group was positively associated with higher tumor mutation burden and PD-L1 expression. Of note, two immunotherapy cohorts demonstrated that patients with low W_Score exhibited long-term clinical benefits and an enhanced immune response. This study is the first to systematically analyze four types of A-related RNA modifications in SKCM, revealing that these "writers" essentially contribute to TME complexity and diversity. We quantitatively evaluated the RNA modification patterns in individual tumors, which could aid in developing personalized immunotherapy strategies for patients.
四种与腺苷（A）相关的RNA修饰（N6-甲基腺苷、N1-甲基腺苷、可变聚腺苷酸化以及A到肌苷的RNA编辑）的“书写者”与包括皮肤黑色素瘤（SKCM）在内的多种癌症类型的肿瘤发生和进展密切相关。然而，这些RNA修饰“书写者”之间在肿瘤微环境（TME）中的相互作用的潜在作用仍不清楚。使用无监督聚类方法识别RNA修饰模式。随后，基于负责上述RNA修饰模式的差异表达基因，构建了一个RNA修饰“书写者”评分模型（W_Score），以量化个体患者中与RNA修饰相关的亚型。此外，还对W_Score与TME特征、临床特征、分子亚型、药物敏感性、免疫反应和预后进行了相关性分析。我们识别出三种RNA修饰模式，它们对应着不同的肿瘤免疫微环境特征和生存结果。根据从与RNA修饰相关的特征基因中提取的W_Score评分，将SKCM患者分为高W_Score组和低W_Score组。低W_Score组的特点是生存结果更好，免疫细胞浸润增强。进一步分析表明，低W_Score组与较高的肿瘤突变负担和PD-L1表达呈正相关。值得注意的是，两个免疫治疗队列表明，低W_Score的患者表现出长期的临床益处和增强的免疫反应。本研究首次系统分析了SKCM中四种与A相关的RNA修饰，揭示了这些“书写者”本质上促成了TME的复杂性和多样性。我们定量评估了个体肿瘤中的RNA修饰模式，这有助于为患者制定个性化的免疫治疗策略。
