Human Papilloma Virus does not fully inactivate p53 in HNSCC

Head and neck squamous cell carcinoma (HNSCC) is a major global health challenge. Inactivation of the tumor suppressor p53 is the most frequent molecular event in this malignancy. p53 inactivation occurs either through TP53 mutations in HPV-negative cases or via HPV-mediated p53 degradation in HPV-positive (HPV+) cases, where most retain a wild-type (WT) TP53 allele. This underscores the critical role of p53-regulated processes in HNSCC pathogenesis. Clinically, HPV+ HNSCC is associated with significantly better outcomes than HPV-negative cases. Despite HPV E6-mediated degradation of p53, 10% of HPV+ HNSCC cases have mutant TP53 alleles, suggesting an additional need to suppress p53 signaling. In this study, we demonstrate that HPV+ TP53 -WT HNSCC cells have residual p53 activity, with tumor-suppressive effects. Specifically, ablation of p53 in HPV+ TP53 -WT HNSCC cells lead to increased proliferation, migration, and invasion. RNA-sequencing revealed that p53 regulates gene transcription (both activation and repression) in the presence of HPV, and we confirmed that these functions are p53-specific. Human tumor data further reveal that among HPV+ HNSCC cases, those with WT TP53 have significantly better survival outcomes than HPV+ cases with TP53 mutations. Notably, HPV+ TP53 -WT HNSCC tumors show decreased PI3K-AKT signaling, increased gene methylation in oncogenic pathways, and fewer chromosomal alterations compared to HPV+ TP53 -mutant tumors. These findings challenge the prevailing notion that p53 is entirely inactivated in HPV+ HNSCC and provide critical insights into HNSCC-specific, p53-driven tumor suppression mechanisms with implications for targeted therapies in HNSCC.