DataSheet_2.xlsx

Abstract

Background: N6-Methyladenosine (m6A), which is prevalent regulator of mRNAs expression, has gathered increasing studies interests. Though the role of m6A is important in many biological processes (such as growth and proliferation of cancers) has been well documented, its potential role in tumor immune microenvironment (TIME) has rarely been analyzed. Methods: We downloaded RNA expression, single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) data from The Cancer Genome Atlas (TCGA). Then we curated 21 m6A regulators and performed nonnegative matrix factorization (NMF) to cluster patients into three m6A subtypes, m6A-related gene subtypes and compared them in overall survival (OS). The combination of CIBERSORT as well as ssGSEA quantified the infiltration levels of immune cells and immune-related functions. The m6A scores were determined by using principal component analysis (PCA) algorithm. Furthermore, we evaluate the correlation of m6A regulators with immune and response to therapy. Results: Three m6A clusters were identified based on the TCGA-HNSCC cohort, and there were significant association among they in overall outcomes and caner-related pathways. We found three m6A clusters were consistent with three phenotypes: immune-inflamed, immune-dessert and immune-excluded. HNSCC patients were divided into high- and low- m6A score groups based on the cutoff of m6A score. Patients with lower m6A score had better overall survival outcome. Further analysis indicated that patients with higher m6A score presented higher tumor mutation burden (TMB). In addition, patients in low m6A score subgroup had high chemotherapeutics sensitivity. GEO cohort confirmed patients with low m6A score demonstrated significant overall survival advantages and clinical benefits.Low m6A score carry a increased neoantigen load, eliciting a response to immunotherapy, and its value in predicting survival outcomes of immunotherapy was also confirmed in three anti-PD-1 cohorts Conclusions: Our study demonstrated m6A regulators is closely related to TIME and the m6A score was an effective prognostic biomarker and predictive indicator for immunotherapy, chemotherapeutics. The comprehensive evaluation of m6A regulators in tumors will extend our understanding on TIME, and effectively guide increasing studies investigations on immunotherapy and chemotherapy strategies for HNSCC.