Identification of m6A Regulator-Associated Methylation Modification Clusters and Immune Profiles in Melanoma

Frontiers in Cell and Developmental Biology

Zhen Fang¹  Xiaokang Li²  Jianjun Yan³  Ningning Dang⁴  Han Li⁶  Xinyu Li⁷  Yan Li⁸  Hao Wu⁹  Xingyu Zhu⁹  Zihao Zhang⁹  Yang Liu⁹  Fengying Du⁹  Qingqing Chu^1,10 

[1] 0Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China;Department of Dermatology, Central Hospital Affiliated to Shandong First Medical University, Jinan, China;Department of Dermatology, Qilu Hospital, Shandong University, Jinan, China;Department of Dermatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China;Department of Gastroenterological Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China;Department of Gastroenterological Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, China;Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China;Department of Respiratory and Critical care, Shandong public health clinical center, Jinan, China;Medical Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China;Outpatient of Podiatric Rehabilitation, Maternity and Child Health Care of Zaozhuang, Zaozhuang, China;

关键词: skin cutaneous melanoma;    methylation of N6 adenosine modification;    tumor microenvironment;    immune profiles;    immunotherapy;   

DOI  :  10.3389/fcell.2021.761134

来源: DOAJ

【 摘 要 】

RNA N6-methyladenosine (m6A) modification in tumorigenesis and progression has been highlighted and discovered in recent years. However, the molecular and clinical implications of m6A modification in melanoma tumor microenvironment (TME) and immune infiltration remain largely unknown. Here, we utilized consensus molecular clustering with nonnegative matrix factorization based on the melanoma transcriptomic profiles of 23 m6A regulators to determine the m6A modification clusters and m6A-related gene signature. Three distinct m6A modification patterns (m6A-C1, C2, and C3), which are characterized by specific m6A regulator expression, survival outcomes, and biological pathways, were identified in more than 1,000 melanoma samples. The immune profile analyses showed that these three m6A modification subtypes were highly consistent with the three known immune phenotypes: immune-desert (C1), immune-excluded (C2), and immune-inflamed (C3). Tumor digital cytometry (CIBERSORT, ssGSEA) algorithm revealed an upregulated infiltration of CD8+ T cell and NK cell in m6A-C3 subtype. An m6A scoring scheme calculated by principal component of m6A signatures stratified melanoma patients into high- and low-m6sig score subgroups; a high score was significantly associated with prolonged survival and enhanced immune infiltration. Furthermore, fewer somatic copy number alternations (SCNA) and PD-L1 expression were found in patients with high m6Sig score. In addition, patients with high m6Sig score demonstrated marked immune responses and durable clinical benefits in two independent immunotherapy cohorts. Overall, this study indicated that m6A modification is involved in melanoma tumor microenvironment immune regulation and contributes to formation of tumor immunogenicity. Comprehensive evaluation of the m6A modification pattern of individual tumors will provide more insights into molecular mechanisms of TME characterization and promote more effective personalized biotherapy strategies.

【 授权许可】

Unknown