Comprehensive Analysis of m6A Regulators Characterized by the Immune Cell Infiltration in Head and Neck Squamous Cell Carcinoma to Aid Immunotherapy and Chemotherapy

Zhiqiang Yang; Xiaoping Ming; Shuo Huang; Minlan Yang; Xuhong Zhou; Jiayu Fang

doi:10.3389/fonc.2021.764798

Comprehensive Analysis of m⁶A Regulators Characterized by the Immune Cell Infiltration in Head and Neck Squamous Cell Carcinoma to Aid Immunotherapy and Chemotherapy

Front Oncol. 2021 Nov 29:11:764798. doi: 10.3389/fonc.2021.764798. eCollection 2021.

Authors

Zhiqiang Yang¹, Xiaoping Ming², Shuo Huang², Minlan Yang², Xuhong Zhou², Jiayu Fang²

Affiliations

¹ Department of Spine Surgery and Musculoskeletal Tumor, Zhongnan Hospital of Wuhan University, Wuhan, China.
² Department of Otorhinolaryngology-Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.

Abstract

Background: N6-Methyladenosine (m⁶A), which is a prevalent regulator of mRNA expression, has gathered increasing study interests. Though the role of m⁶A as being 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 polymorphism (SNP), and copy number variation (CNV) data from The Cancer Genome Atlas (TCGA). We then curated 21 m⁶A regulators and clustered patients into three m⁶A subtypes and m⁶A-related gene subtypes and compared them based on 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 associations among them in overall outcomes and caner-related pathways. We found that 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 an 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 that m⁶A regulators are closely related to TIME and the m⁶A score was an effective prognostic biomarker and predictive indicator for immunotherapy and chemotherapeutics. Comprehensive evaluation of m⁶A regulators in tumors will extend our understanding of TIME and effectively guide increasing study investigations on immunotherapy and chemotherapy strategies for HNSCC.

Keywords: HNSCC; TIME; m6A regulator; m6A score; therapy.