Abstract
BACKGROUND: Numerous studies have shown that the aging microenvironment played a huge impact on tumor progression. However, the clinical prognostic value of aging-related risk signatures and their effects on the tumor immune microenvironment (TIME) in head and neck squamous cell carcinoma (HNSCC) remains largely unclear. This study aimed to identify novel prognostic signatures based on aging-related genes (AGs) and reveal the landscape of the TIME in HNSCC. METHODS: Differentially expressed AGs were identified using the gene set enrichment analysis (GSEA). The prognostic risk model of AGs was established by univariate and multivariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses. The independent prognostic value of the risk model and the correlations of the prognostic signature with immune score, tumor immune cell infiltration, and immune checkpoints were systematically analyzed. RESULTS: A prognostic risk model of four AGs (BAK1, DKK1, CDKN2A, and MIF) was constructed and validated in the training and testing datasets. Kaplan-Meier curves and time-dependent receiver operating characteristic (ROC) curve analysis confirmed that the four-AG risk signature possessed an accurate predictive value for the prognosis of patients with HNSCC. Correlation analysis revealed that the risk score was negatively associated with immune score and immune cell infiltration level while positively correlated with immune checkpoint blockade (ICB) response score. Patients of the high-risk subtype contained higher infiltration levels of resting natural killer (NK) cells, M0 macrophages, M2 macrophages, and resting mast cells while having lower infiltration levels of memory B cells, CD8+ T cells, follicular helper T cells, regulatory T cells (Tregs), and activated mast cells than did those of the low-risk subtype. The expressions of CTLA4, PDCD1, and TIGIT were downregulated while the PDCD1LG2 expression was upregulated in the high-risk subtype compared to those in the low-risk subtype. Furthermore, the four selected AGs in the risk model were demonstrated to possess important functions in immune cell infiltration and ICB response of HNSCC. CONCLUSIONS: The aging-related risk signature is a reliable prognostic model for predicting the survival of HNSCC patients and provides potential targets for improving outcomes of immunotherapy.