Abstract
BackgroundThe role of RNA N6-methyladenosine (m6A) modification in tumor progression and metastasis has been demonstrated. Nonetheless, potential biological function of m6A modification patterns in nasopharyngeal carcinoma (NPC) remains unknown.MethodsThe m6A modification patterns were comprehensively evaluated based on 26 m6A regulators in NPC, and m6A subtype and also m6A score were identified and systematically correlated with representative tumor characteristics.ResultsTwo distinct m6A subtypes were determined and were highly consistent with immune activated and immune suppressed phenotypes, respectively. More representative m6A scores of individual tumors could predict tumor microenvironment (TME) infiltration, mRNA based stemness index (mRNAsi), EBV gene expression, genetic variation, and prognosis of NPC patients. Low m6A score, characterized by activation of immunity and suppression of mRNAsi and EBV gene, indicated an activated TME phenotype and better PFS and also lower risk of recurrence and metastasis. High m6A score, characterized by activation of Wnt and NF-κB signaling pathway and lack of effective immune infiltration, indicated an immune suppressed TME phenotype and poorer survival. Low m6A score was also correlated with increased tumor mutation burden (TMB) and better response to immunotherapy, and vice versa. A significant therapeutic advantage in patients with low m6A score was confirmed with an anti-PDL1 immunotherapy cohort.Conclusionsm6A patterns played an important role in the diversity and complexity of TME. m6A score could be used to evaluate the m6A pattern of individual tumor to enhance our understanding of TME infiltration and guide more effective immunotherapy strategies.
Highlights
Nasopharyngeal carcinoma (NPC), deriving from squamous epithelial cells of the nasopharyngeal mucosa, is the most common malignant tumor in the head and neck and endemic in South China and Southeast Asia [1]
The immunotherapeutic cohort of metastatic urothelial cancer patients treated with an anti-PDL1 antibody atezolizumab (IMvigor210 cohort) was used as the validation cohort [19], and the expression data and detailed m6A Score for Nasopharyngeal Carcinoma clinical annotations were obtained from http://research-pub
Differential gene expression analysis conducted in 5 Gene Expression Omnibus (GEO) datasets (GSE64634, GSE12452, GSE13597, GSE34573, and GSE53819) between NPC samples and normal control samples revealed that most of the m6A regulators were highly expressed in NPC with the criterion of log2FC >1 and FDR >0.05 (Figure 2B and Figure S1A)
Summary
Nasopharyngeal carcinoma (NPC), deriving from squamous epithelial cells of the nasopharyngeal mucosa, is the most common malignant tumor in the head and neck and endemic in South China and Southeast Asia [1]. An Epstein–Barr virus (EBV) infection is deemed as a primary etiological factor for NPC [3], and this virus-associated cancer represents the typical “inflamed tumor” which exhibits abundant infiltrating immune cells in the tumor microenvironment (TME) [4]. These features make immunotherapy a promising treatment for NPC patients. To further improve the efficacy of immunotherapy in NPC, it is quite urgent to analyze the TME to better identify the mechanism underlying the low response to ICIs. The role of RNA N6-methyladenosine (m6A) modification in tumor progression and metastasis has been demonstrated. Potential biological function of m6A modification patterns in nasopharyngeal carcinoma (NPC) remains unknown
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