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

被引：3

作者：

Mourtada, Jana ^{[1
,2
]}

Lony, Christelle ^{[1
,2
]}

Nicol, Anais ^{[3
]}

De Azevedo, Justine ^{[1
,2
]}

Bour, Cyril ^{[1
,2
]}

Macabre, Christine ^{[1
,2
,4
]}

Roncarati, Patrick ^{[5
]}

Ledrappier, Sonia ^{[4
]}

Schultz, Philippe ^{[6
]}

Borel, Christian ^{[7
]}

Burgy, Mickael ^{[7
]}

Wasylyk, Bohdan ^{[8
,9
,10
,11
]}

Mellitzer, Georg ^{[2
]}

Herfs, Michael ^{[5
]}

Gaiddon, Christian ^{[2
]}

Jung, Alain C. ^{[1
,2
,4
]}

机构：

[1] Inst Cancerol Strasbourg Europe, Lab Biol Tumorale, Strasbourg, France

[2] Univ Strasbourg, Lab Streinth, UMR S 1113 IRFAC, Inserm, Strasbourg, France

[3] Inst Cancerol Strasbourg Europe, Lab Radiobiol, Strasbourg, France

[4] Tumorotheque Ctr Paul Strauss, Ctr Paul Strauss, Strasbourg, France

[5] Univ Liege, Lab Expt Pathol, GIGA Canc, Liege, Belgium

[6] Hop Univ Strasbourg, Dept Otorhinolaryngol & Head & Neck Surg, Strasbourg, France

[7] Inst Cancerol Strasbourg Europe, Dept Med Oncol, Strasbourg, France

[8] Inst Genet & Biol Mol & Cellulaire IGBMC, Dept Funct Genom & Canc, Illkirch Graffenstaden, France

[9] Inst Natl St & Rech Medicale INSERM, U 1258, Illkirch Graffenstaden, France

[10] Ctr Natl Rech Sci CNRS, UMR 7104, Illkirch Graffenstaden, France

[11] Univ Strasbourg, Strasbourg, France

来源：

FRONTIERS IN IMMUNOLOGY | 2023年 / 14卷

关键词：

Delta Np63; immune response; human papillomavirus; oropharyngeal squamous cell carcinoma; tumor microenvironment; SQUAMOUS-CELL CARCINOMA; NF-KAPPA-B; HUMAN-PAPILLOMAVIRUS; OROPHARYNGEAL CARCINOMA; MICRORNA; 203; P63; EXPRESSION; DELTA-NP63-ALPHA; PATHWAY; DIFFERENTIATION;

D O I：

10.3389/fimmu.2023.1264093

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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 Delta Np63 dependent molecular signature that is associated with patient prognosis. Delta Np63 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 Delta Np63 expression levels correlate with an enhanced anti-tumor immune environment in OSCC, and Delta Np63 promotes cancer cell phagocytosis by macrophages through a DKK3/NF-kappa B-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.

引用

页数：18