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

Abstract

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.

Epigenetic Mechanisms Underlying Melanoma Resistance to Immune and Targeted Therapies

“…Melanoma tumorigenesis and progression has been linked to dysregulation of epigenetic mechanisms, such as chromatin remodeling complexes (INO80 [ 59 , 60 ], ISWI [ 61 , 62 ], and SWI/SNF [ 63 , 64 , 65 ]); histone post-translational modifications (PTMs) by histone acetyltransferases (HATs) [ 66 ], deacetylases (HDACs) [ 67 ], methyltransferases (HMTs) [ 68 ], and demethylases (HDMs) [ 69 ]; histone variants [ 70 , 71 , 72 ]; DNA [ 73 , 74 , 75 ] and RNA [ 76 , 77 , 78 ] methylation; plus non-coding [ 79 , 80 , 81 , 82 ], micro- [ 83 , 84 , 85 ], and circular [ 86 , 87 , 88 ] RNA. Unsurprisingly, epigenetic changes are also linked to immune [ 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 ] and targeted [ 98 , 99 , 100 , 101 , 102 , 103 ] therapy resistance. Therapy resistance develops rapidly and is unlikely to be driven by de novo mutations [ 17 , 104 ].…”

N6‐methyladenosine functions and its role in skin cancer

“…To identify m6A modification clusters and m 6 A-related gene signatures, consensus molecular clustering with non-negative matrix factorization based on the melanoma transcriptomic profiles of 23 m6A regulators was applied to more than 1000 melanoma samples and showed that m6A modifications were involved in melanoma TME immunoregulation and facilitated tumour immunogenicity development. 70,71 Significant differences in tumour-associated immune infiltration between two m6A clusters were identified by analysing the m6A cluster and immune infiltration phenotypes in public datasets. 72 Anti-tumour immune responses were exerted by innate and adaptive immune cells, such as macrophages, polymorphonuclear neutrophils, natural killer cells and dendritic cells (DCs) in the TME.…”

“…m6A modification roles have been identified in the melanoma tumour microenvironment (TME), with immune infiltration roles gradually uncovered. To identify m6A modification clusters and m 6 A‐related gene signatures, consensus molecular clustering with non‐negative matrix factorization based on the melanoma transcriptomic profiles of 23 m6A regulators was applied to more than 1000 melanoma samples and showed that m6A modifications were involved in melanoma TME immunoregulation and facilitated tumour immunogenicity development 70,71 . Significant differences in tumour‐associated immune infiltration between two m6A clusters were identified by analysing the m6A cluster and immune infiltration phenotypes in public datasets 72 .…”

Integrated analysis from multi-center studies identities m7G-derived modification pattern and risk stratification system in skin cutaneous melanoma

“…This means that immunotherapy may preferentially benefit patients with substantial CD8+ T infiltration in the TME. Therefore, predicting response to ICIs based on the characteristics of TME is a critical step to improve response to existing ICIs therapy ( 7 ).…”