Abstract
BackgroundN6-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.MethodsWe 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.ResultsThree 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.ConclusionsOur 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.
Highlights
Head and neck squamous cell carcinoma (HNSCC) remains the primary cause of cancer death worldwide, with approximately 890,000 newly diagnosed cases per year [1]
Most modification of the N6 adenosine (m6A) regulators showed the prevalent deletions in copy number, while insulinlike growth factor 2 mRNA-binding protein 2 (IGF2BP2), YTH domaincontaining 1 (YTHDC1), and CBLL1 had a widespread frequency of copy number variation (CNV) amplification (Figure 1C)
We further demonstrated that the expressions of alkB homolog 5 (ALKBH5), METTL3, YTHDF2, and YTHDC2 were significantly downregulated in tumor samples, and in contrast the expression of CBLL1, METTL14, IGF2BP2, IGF2BP3, KIAA1429, YTHDF1, and YTHDC1 were significantly upregulated in tumor samples (Figure 1E)
Summary
Head and neck squamous cell carcinoma (HNSCC) remains the primary cause of cancer death worldwide, with approximately 890,000 newly diagnosed cases per year [1]. Conventional treatments include surgery, radiotherapy, and chemotherapy based on the stage of patients, but most HNSCC exhibit weak prognosis because of the complex mechanisms whereby the RNA modifications were associated with different immune cell infiltrations. Immunotherapy may provide significant therapeutic effects in identifying and eliminating tumor cells by activating patients’ immune defense system [3]. This treatment yields new insights with unparalleled and synergistic survival benefits into multiple clinical management [4, 5]. The regulatory mechanism and the novel markers of HNSCC should be urgently investigated by comprehensively parsing the components of TIME so that the ideal HNSCC subgroups for guiding and predicting therapeutic responsiveness could be identified. 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
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