Comprehensive Analysis Of Tumor Microenvironment And Prognosis Associated With Ferroptosis Signature For Head And Neck Squamous Cell Carcinoma

PurposeHead and neck squamous cell carcinoma(HNSCC)has a poor prognosis due to its high rates of recurrence and metastasis.Ferroptosis is a novel type of programmed cell death induced by iron-dependent lipid peroxidation,which plays an important role in cancer development and treatment.However,the prognostic value of ferroptosis-related genes in head and neck squamous cell carcinoma remains to be further elucidated.MethodsIn this study,we comprehensively analyzed the relationship between ferroptosis genes and immune cell infiltration in head and neck squamous cell carcinoma(training set: TCGA,n=468,validation set: GEO,n=97).Differences in prognosis,immune scores and signaling pathway enrichment were compared across molecular subtypes by consistent clustering analysis.A risk score prognostic model was constructed using stepwise regression analysis.TCGA patients were divided into high-risk and low-risk groups according to median risk score,and the Kaplan-Meier method was used to compare the survival differences between the two groups and then we performed an independent prognostic analysis of risk score and clinical features.External validation was performed using the GEO dataset.Response to immunotherapy and chemotherapy was predicted for different risk groups based on TIDE scores and GDSC database of three commonly used chemotherapeutic agents.To explore the survival mechanisms and therapeutic targets of the prognostic model,we compared the clinical features of different risk groups and correlated risk score with immune cells and immunomodulatory genes.CHARacterizing Tumor Subpopulations was used to identify TME-associated molecular targets at a single-cell resolution.ResultsThe TCGA cohort was divided into two subgroups(Cluster1 and Cluster2)using consensus clustering analysis.With better prognosis,Cluster1 exhibited increased immune scores and more immune cell infiltration.Signaling pathways such as angiogenesis,PI3K/AKT/m TOR,hypoxia and epithelial mesenchymal transition were significantly enriched in Cluster2.A prognostic model was constructed using seven ferroptosis-related genes screened by stepwise regression analysis.The overall survival(OS)of patients in the low-risk group was significantly better than those in the high-risk group(TCGA: P < 0.001,GEO: P < 0.001).Risk score was an independent predictor of OS in a multivariate Cox regression analysis(HR > 1,P < 0.001).Time-dependent ROC curve analysis suggested that the model had good predictive power.The risk model was further validated in the GEO validation set.Patients in the high-risk group had significantly higher TIDE scores compared with those in the low-risk group,but the half-maximal inhibitory concentration(IC50)of paclitaxel,docetaxel and cisplatin were lower than those in the low-risk group.Predictive analysis suggested that the high-risk score group was sensitive to chemotherapy,while the low-risk group could potentially benefit from immunotherapy.Risk scores were markedly higher in patients with tumor,advanced stage,positive margin status,perineural invasion and lymphovascular invasion.Also,risk score was correlated with T/B cells and three immunomodulatory genes(CD27,CD276 and CD40LG),where CD276 was positively associated with risk score and suggested a poor prognosis.Single-cell analysis showed CD276 was highly expressed in fibroblasts that significantly enriched in the angiogenesis and epithelial mesenchymal transition pathways,suggesting that CD276 may be a potential therapeutic target in high-risk patients.ConclusionThe prognostic model based on seven ferroptosis-related genes prognostic model can effectively predict the survival of HNSCC patients,providing a novel and effective method to assess the prognosis of HNSCC patients and prolong their survival through individualized treatment.