Comprehensive Analysis of the PD-L1 and Immune Infiltrates of mA RNA Methylation Regulators in Head and Neck Squamous Cell Carcinoma.

Because most studies have focused on the intrinsic carcinogenic pathways of tumors, the underlying role of N6-methyladenosine (mA) methylation in tumor immune microenvironment (TIME) remains elusive. Herein, we systematically explored the correlations of prominent mA regulators with PD-L1 and immune infiltrates in 769 head and neck squamous cell carcinomas (HNSCCs; The Cancer Genome Atlas [TCGA] cohort, n = 499; GSE65858 cohort, n = 270). The PD-L1 expression evidently associated with mA regulators. Two molecular subtypes (cluster1/2) were identified by consensus clustering for 15 mA regulators. The cluster2 preferentially associated with favorable prognosis, upregulated PD-L1 expression, higher immunoscore, and distinct immune cell infiltration. The hallmarks of G2M checkpoint, mTORC1 signaling, and PI3K/AKT/mTOR signaling were remarkably enriched in the cluster1. A prognostic risk score was constructed using seven mA regulator-associated signatures that represented an independent prognosis factor for HNSCC. Patients with low-risk score exhibited higher immunoscore and upregulated PD-L1 expression than patients with high-risk score. Consistently, mA regulators showed the same influence on immune modulation and survival in external GSE65858 cohort. Further analysis revealed that mA regulator-based signatures were implicated in TIME and their copy-number alterations dynamically affected the abundance of tumor-infiltrating immune cells. Collectively, our study elucidated the important role of mA methylation in TIME of HNSCC. The proposed mA regulator-based signatures might serve as crucial mediators of TIME in HNSCC, representing promising therapeutic targets in improving immunotherapeutic efficacy.