Identification and Biological Validation of a Chemokine/Chemokine Receptor-Based Risk Model for Predicting Immunotherapeutic Response and Prognosis in Head and Neck Squamous Cell Carcinoma

Over 80% of head and neck squamous cell carcinoma (HNSCC) patients failed to respond to immunotherapy, which can likely be attributed to the tumor microenvironment (TME) remolding mediated by chemokines/chemokine receptors (C/CR). This study aimed to establish a C/CR-based risk model for better immunotherapeutic responses and prognosis. After assessing the characteristic patterns of the C/CR cluster from the TCGA-HNSCC cohort, a six-gene C/CR-based risk model was developed to stratify patients by LASSO Cox analysis. The screened genes were multidimensionally validated by RT-qPCR, scRNA-seq, and protein data. A total of 30.4% of patients in the low-risk group had better responses to anti-PD-L1 immunotherapy. A Kaplan–Meier analysis showed that patients in the low-risk group had longer overall survival. A time-dependent receiver operating characteristic curve and Cox analyses indicated that risk score served as an independent predictive indicator. The robustness of the immunotherapy response and prognosis prediction was also validated in independent external datasets. Additionally, the TME landscape revealed that the low-risk group was immune activated. Furthermore, the cell communication analysis on the scRNA-seq dataset revealed that cancer-associated fibroblasts were the main communicators within the C/CR ligand–receptor network of TME. Collectively, The C/CR-based risk model simultaneously predicted immunotherapeutic response and prognosis, potentially optimizing personalized therapeutic strategies of HNSCC.