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Aim:  The aim of our study was to investigate the potential predictive value of the combination of radiosensitivity gene signature and PD-L1 expression for the prognosis of locally advanced head and neck squamous cell carcinoma (HNSCC).   Methods:  The cohort was selected from The Cancer Genome Atlas (TCGA) and classified into the radiosensitive (RS) group and radioresistant (RR) group by a radiosensitivity-related gene signature. The cohort was also grouped as PD-L1-high or PD-L1-low based on PD-L1 mRNA expression. The least absolute shrinkage and selection operator (lasso)-based Cox model was used to select hub survival genes. An independent validation cohort was obtained from the Gene Expression Omnibus (GEO) database.   Results:  We selected 288 locally advanced HNSCC patients from TCGA. The Kaplan–Meier method found that the RR and PD-L1-high group had a worse survival than others ( p  = 0.033). The differentially expressed gene (DEG) analysis identified 553 upregulated genes and 486 downregulated genes ( p  &amp;lt; 0.05, fold change &amp;gt;2) between the RR and PD-L1-high group and others. The univariate Cox analysis of each DEG and subsequent lasso-based Cox model revealed five hub survival genes ( POU4F1 ,  IL34 ,  HLF ,  CBS , and  RNF165 ). A further hub survival gene-based risk score model was constructed, which was validated by an external cohort. We observed that a higher risk score predicted a worse prognosis ( p  = 0.0013). The area under the receiver operating characteristic curve (AUC) plots showed that this risk score model had good prediction value (1-year AUC = 0.684, 2-year AUC = 0.702, and 3-year AUC = 0.688). Five different deconvolution methods all showed that the B cells were lower in the RR and PD-L1-high group ( p  &amp;lt; 0.05). Finally, connectivity mapping analysis showed that the histone deacetylase (HDAC) inhibitor trichostatin A might have the potential to reverse the phenotype of RR and PD-L1-high in locally advanced HNSCC ( p  &amp;lt; 0.05, false discovery rate &amp;lt;0.1).   Conclusion:  The combination of 31-gene signature and the PD-L1 mRNA expression had a potential predictive value for the prognosis of locally advanced HNSCC who had RT. The B cells were lower in the RR and PD-L1-high group. The identified risk gene signature of locally advanced HNSCC and the potential therapeutic drug trichostatin A for the RR and PD-L1-high group are worth being further studied in a prospective homogenous cohort.

frontiers in molecular biosciences

Combination of Radiosensitivity Gene Signature and PD-L1 Status Predicts Clinical Outcome of Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma: A Study Based on The Cancer Genome Atlas Dataset