Pinpointing the decisive role of TP53 mutations in orchestrating immunosuppression in head and neck squamous cell carcinoma

Abstract

Abstract Background The head and neck squamous cell carcinoma (HNSCC) is the sixth common cancer worldwide and can be affected by multiple etiological factors. The immuno-combination therapies recently demonstrated superior performance but efficient biomarkers for outcome prediction is still lacking. Genetically, TP53 gene demonstrated highest alternation frequency in HNSCC. The lucid elaboration on the interconnections between tumor micro-environment (TME) composition, tumor molecular status and immunotherapy response could benefit HNSCC disease control. Methods Multi-omics data for HNSCC including DNA somatic mutation, DNA copy number variation (CNV), RNA expression, DNA methylation as well as patient survival information was collected from The Cancer Genome Atlas (TCGA) project and compared between patients stratified by TP53 mutations. Key discoveries were validated experimentally by patient samples and computationally by public HNSCC cohorts. Results The TP53 gene demonstrated top alternation frequency (63%, 298/473) and conferred significant detrimental effect on patient survival. As for expressional analysis, the top down-regulated differentially expressed genes (DEGs) in TP53 mutant group (TP53MT) exhibited power in survival stratification. Interestingly, the CD8+ T cell specifically showed infiltration level diminution in TP53MT group, which was highly correlated with the top DEGs in TP53MT population. Similarly, top CpG sites hypermethylated and the cytoband as well as genes possessing significantly amplified copy number in TP53MT demonstrated the capacity to affect patient survival and strong associations with an immunosuppressive TME. These findings were validated by immunohistochemistry (IHC) method in 14 HNSCC patients and four HNSCC public cohorts. Conclusions Our study identified sets of essential molecules altered by TP53 mutational abnormality in HNSCC, which all exhibited strong associations with an immunosuppressive TME. These discoveries provide an unprecedented perspective for HNSCC patient personalized treatment scheme formulation.