human papillomavirus; immune response; oropharyngeal squamous cell carcinoma; tumor microenvironment; ΔNp63; Humans; Human Papillomavirus Viruses; Prognosis; Squamous Cell Carcinoma of Head and Neck/genetics; Papillomavirus Infections/complications; Carcinoma, Squamous Cell; Head and Neck Neoplasms/genetics; Immunology; Immunology and Allergy
Abstract :
[en] [en] 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.
Disciplines :
Oncology
Author, co-author :
Mourtada, Jana; Laboratoire de Biologie Tumorale, Institut de cancérologie Strasbourg Europe, Strasbourg, France ; Université de Strasbourg-Inserm, UMR_S 1113 IRFAC, Laboratory « Streinth », Strasbourg, France
Lony, Christelle; Laboratoire de Biologie Tumorale, Institut de cancérologie Strasbourg Europe, Strasbourg, France ; Université de Strasbourg-Inserm, UMR_S 1113 IRFAC, Laboratory « Streinth », Strasbourg, France
Nicol, Anaïs; Laboratoire de Radiobiologie, Institut de cancérologie Strasbourg Europe, Strasbourg, France
De Azevedo, Justine; Laboratoire de Biologie Tumorale, Institut de cancérologie Strasbourg Europe, Strasbourg, France ; Université de Strasbourg-Inserm, UMR_S 1113 IRFAC, Laboratory « Streinth », Strasbourg, France
Bour, Cyril; Laboratoire de Biologie Tumorale, Institut de cancérologie Strasbourg Europe, Strasbourg, France ; Université de Strasbourg-Inserm, UMR_S 1113 IRFAC, Laboratory « Streinth », Strasbourg, France
Macabre, Christine; Laboratoire de Biologie Tumorale, Institut de cancérologie Strasbourg Europe, Strasbourg, France ; Université de Strasbourg-Inserm, UMR_S 1113 IRFAC, Laboratory « Streinth », Strasbourg, France ; Tumorothèque du Centre Paul Strauss, Centre Paul Strauss, Strasbourg, France
RONCARATI, Patrick ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'anatomie et cytologie pathologiques
Ledrappier, Sonia; Tumorothèque du Centre Paul Strauss, Centre Paul Strauss, Strasbourg, France
Schultz, Philippe; Hôpitaux Universitaires de Strasbourg, Department of Otorhinolaryngology and Head and Neck Surgery, Strasbourg, France
Borel, Christian; Department of Medical Oncology, Institut de cancérologie Strasbourg Europe, Strasbourg, France
Burgy, Mickaël; Department of Medical Oncology, Institut de cancérologie Strasbourg Europe, Strasbourg, France
Wasylyk, Bohdan; Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch-Graffenstaden, France ; Institut National de la Santé et de la Recherche Médicale (INSERM) U 1258, Illkirch-Graffenstaden, France ; Centre Nationale de la Recherche Scientifique (CNRS) UMR 7104, Illkirch-Graffenstaden, France ; Université de Strasbourg, Strasbourg, France
Mellitzer, Georg; Université de Strasbourg-Inserm, UMR_S 1113 IRFAC, Laboratory « Streinth », Strasbourg, France
Herfs, Michael ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Gaiddon, Christian; Université de Strasbourg-Inserm, UMR_S 1113 IRFAC, Laboratory « Streinth », Strasbourg, France
Jung, Alain C; Laboratoire de Biologie Tumorale, Institut de cancérologie Strasbourg Europe, Strasbourg, France ; Université de Strasbourg-Inserm, UMR_S 1113 IRFAC, Laboratory « Streinth », Strasbourg, France ; Tumorothèque du Centre Paul Strauss, Centre Paul Strauss, Strasbourg, France
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