Background: Deconvoluting the heterogenous prognosis of Human Papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OSCC) is crucial for enhancing patient care, given its rapidly increasing incidence in western countries and the adverse side effects of OSCC treatments.
Methods: Transcriptomic data from HPV-positive OSCC samples were analyzed using unsupervised hierarchical clustering, and clinical relevance was evaluated using Kaplan-Meier analysis. HPV-positive OSCC cell line models were used in functional analyses and phenotypic assays to assess cell migration and invasion, response to cisplatin, and phagocytosis by macrophages in vitro.
Results: We found, by transcriptomic analysis of HPV-positive OSCC samples, a ΔNp63 dependent molecular signature that is associated with patient prognosis. ΔNp63 was found to act as a tumor suppressor in HPV-positive OSCC at multiple levels. It inhibits cell migration and invasion, and favors response to chemotherapy. RNA-Seq analysis uncovered an unexpected regulation of genes, such as DKK3, which are involved in immune response-signalling pathways. In agreement with these observations, we found that ΔNp63 expression levels correlate with an enhanced anti-tumor immune environment in OSCC, and ΔNp63 promotes cancer cell phagocytosis by macrophages through a DKK3/NF-κB-dependent pathway.
Conclusion: Our findings are the first comprehensive identification of molecular mechanisms involved in the heterogeneous prognosis of HPV-positive OSCC, paving the way for much-needed biomarkers and targeted treatment.
Keywords: human papillomavirus; immune response; oropharyngeal squamous cell carcinoma; tumor microenvironment; ΔNp63.
Copyright © 2023 Mourtada, Lony, Nicol, De Azevedo, Bour, Macabre, Roncarati, Ledrappier, Schultz, Borel, Burgy, Wasylyk, Mellitzer, Herfs, Gaiddon and Jung.