A novel ΔNp63-dependent immune mechanism improves prognosis of HPV-related head and neck cancer

Frontiers in Immunology

Immunology

Bohdan Wasylyk¹  Christian Borel²  Mickaël Burgy²  Philippe Schultz³  Jana Mourtada⁴  Justine De Azevedo⁴  Christelle Lony⁴  Cyril Bour⁴  Christine Macabre⁵  Alain C. Jung⁵  Anaïs Nicol⁶  Patrick Roncarati⁷  Michaël Herfs⁷  Sonia Ledrappier⁸  Georg Mellitzer⁹  Christian Gaiddon⁹ 

[1] 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;Department of Medical Oncology, Institut de cancérologie Strasbourg Europe, Strasbourg, France;Hôpitaux Universitaires de Strasbourg, Department of Otorhinolaryngology and Head and Neck Surgery, Strasbourg, France;Laboratoire de Biologie Tumorale, Institut de cancérologie Strasbourg Europe, Strasbourg, France;Université de Strasbourg-Inserm, UMR_S 1113 IRFAC, Laboratory « Streinth », Strasbourg, France;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;Laboratoire de Radiobiologie, Institut de cancérologie Strasbourg Europe, Strasbourg, France;Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège, Liège, Belgium;Tumorothèque du Centre Paul Strauss, Centre Paul Strauss, Strasbourg, France;Université de Strasbourg-Inserm, UMR_S 1113 IRFAC, Laboratory « Streinth », Strasbourg, France;

关键词: ΔNp63;    immune response;    human papillomavirus;    oropharyngeal squamous cell carcinoma;    tumor microenvironment;   

DOI  :  10.3389/fimmu.2023.1264093

 received in 2023-07-20, accepted in 2023-09-29,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundDeconvoluting 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.MethodsTranscriptomic 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.ResultsWe 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.ConclusionOur 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.

【 授权许可】

Unknown   
Copyright © 2023 Mourtada, Lony, Nicol, De Azevedo, Bour, Macabre, Roncarati, Ledrappier, Schultz, Borel, Burgy, Wasylyk, Mellitzer, Herfs, Gaiddon and Jung