Reflux May Weaken Therapeutic Effect of Immune Checkpoint Inhibitors on Head and Neck Squamous Cell Carcinoma: A Proposed Risk Prediction Model Based on LPR/GERD-Related Genes

Abstract

Laryngopharyngeal reflux (LPR) and gastroesophageal reflux disease (GERD) involve in head and neck diseases. Their association with carcinogenesis of head and neck squamous cell carcinoma (HNSCC) has attracted increasing attention in recent years. We established a risk prediction model based on LPR/GERD-related genes (RRGs), to investigate the relationship between LPR/GERD and HNSCC, and explore their relevant mechanisms. To establish the risk model, the TCGA-HNSC project from the Cancer Genome Atlas (TCGA) database was used to conduct training and internal validation assays, and the GSE65858 project and five other TCGA projects involving different kinds of tumors were used to conduct the external validation assays. Twelve RRGs were determined to construct risk signature. Kaplan–Meier curves and receiver operating characteristic curves for the model were used to predict 1-, 3-, and 5-year overall survival (OS), particularly for patients with laryngeal squamous cell carcinoma (LSCC). The proportions of immune cells in high-risk group, including T cells, CD8+ T cells, NK cells, myeloid dendritic cells, B lineage, and monocytic lineage, were significantly lower ( P <0.05). Interestingly, risk score was negatively associated with immune checkpoint-related genes expression. The predicted therapeutic sensitivity of immune checkpoint inhibitors (ICIs) in high-risk group was lower (7.27±1.08 vs. 7.80±1.12, P = 4.6×10 −6 ). Moreover, the predicted IC50 of Erlotinib (EGFR inhibitor) and Parthenolide (NF- κ B inhibitor) was lower in high-risk group ( P = 2.6×10 −12 and 2.7×10 −7 , respectively). LPR/GERD may shorten the OS of HNSCC, especially LSCC. The most important finding from this study is that, the HNSCC patients suffering from LPR/GERD benefit less from ICIs.