Abstract
BACKGROUND: Regulatory B cells (Bregs) are critical in regulating immune responses and fostering immune tolerance in various cancers; however, their role in head and neck squamous cell carcinoma (HNSCC) is unclear. This study examined the function of Breg-related genes in HNSCC and their possible prognostic and therapeutic implications. METHODS: The Cancer Genome Atlas (TCGA)-HNSCC training cohort was used to establish a prognostic signature for Breg-related genes by applying consensus clustering, univariate Cox regression, least absolute shrinkage and selection operator (LASSO) Cox regression, and multivariate Cox regression analyses. Validation cohorts from the TCGA and Gene Expression Omnibus (GEO) databases were used to assess the robustness of the model. This study investigated the associations among the signature and several clinicopathological features, expression of immune checkpoints, tumor mutation burden (TMB), and sensitivity to pharmacological agents. The underlying mechanisms were examined using weighted gene co-expression network analysis (WGCNA) and gene set enrichment analysis (GSEA). Additionally, various techniques, including ESTIMATE, were used to assess immune infiltration. Functional experiments and transcriptome sequencing were conducted to investigate the role of oxidized low-density lipoprotein receptor 1 (OLR1) gene. RESULTS: The analysis identified an eight-gene Breg-related prognostic signature that demonstrated robust predictive power across cohorts. High-risk patients exhibited significantly poorer survival, reduced immune cell infiltration, and lower immune molecule expression. The prognostic accuracy was further improved by integrating the risk score with TMB or clinicopathological features. Functional analyses revealed strong associations with immune-related pathways. Moreover, the signature was reported as a potential biomarker for predicting immunotherapy response and drug sensitivity. Furthermore, OLR1, the most essential gene of the signature, was found to be oncogenic and linked to immune evasion in HNSCC. CONCLUSIONS: The Breg-related gene signature provides an effective prognostic tool for patients with HNSCC, reflects the immune landscape and TMB, and may direct personalized therapeutic approaches, such as immunotherapy.