Increased response to TPF chemotherapy promotes immune escape in hypopharyngeal squamous cell carcinoma

Background: There is an urgent need to identify which patients would benefit from TPF chemotherapy in hypopharyngeal squamous cell carcinoma (HPSCC) and to explore new combinations to improve the treatment effect. Materials and methods: Gene-expression profiles in 15 TPF-sensitive patients were compared to 13 resistant patients. Immunohistochemistry (IHC) was performed to detect CD8⁺ T cells in 28 samples. Patient-Derived Tumor Xenograft (PDX) model and IHC were used to verify markers that optimize treatment for HPSCC. Results: Through RNA sequencing 188 genes were up-regulated in TPF chemotherapy-resistant (CR) tissues were involved in T cell activation, while 60 down-regulated genes were involved in glycolysis. Gene set enrichment analysis (GSEA) showed that chemotherapy-sensitive (CS) group upregulation of the pathways of glycolysis, while immune response was downregulated. CIBERSORT, MCP-counter, and IHC proved that most immune cells including CD8⁺ T cells in the CR significantly higher than that in CS group. Among the 16 up-regulated genes in CS had close associations, the most significant negative correlation between the gene level and CD8⁺ T cells existed in SEC61G. SEC61G was related to glycolysis, which was transcriptionally regulated by E2F1, and participated in antigen degradation through ubiquitin-dependent protein catabolic process. Palbociclib, combined with Cetuximab decreased the tumor burden and significantly suppressed the expression of E2F1 and SEC61G while activating MHC-I in PDX model. Conclusion: Enhanced glycolysis promoted immune escape, but increased response to TPF chemotherapy. SEC61G was the center of the molecular network and targeting the E2F1/SEC61G pathway increased the expression level of MHC-I.