DataSheet_1_A novel ΔNp63-dependent immune mechanism improves prognosis of HPV-related head and neck cancer.pdf

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.

背景 鉴于人乳头瘤病毒（Human Papillomavirus, HPV）相关口咽鳞状细胞癌（oropharyngeal squamous cell carcinoma, OSCC）在西方国家的发病率持续快速攀升，且该肿瘤的治疗手段存在诸多不良反应，厘清其异质性预后特征对于优化患者诊疗工作具有重要意义。
方法 本研究采用无监督层次聚类分析法对HPV阳性OSCC样本的转录组数据进行分析，并通过Kaplan-Meier分析法评估其临床相关性。同时，利用HPV阳性OSCC细胞系模型开展功能分析与表型实验，以检测细胞迁移与侵袭能力、顺铂应答反应，以及体外巨噬细胞对肿瘤细胞的吞噬作用。
结果 通过对HPV阳性OSCC样本的转录组分析，本研究鉴定出一条与患者预后相关的、依赖ΔNp63的分子特征谱。研究发现，ΔNp63在HPV阳性OSCC中发挥多重肿瘤抑制作用：它可抑制细胞迁移与侵袭，并增强肿瘤细胞对化疗的敏感性。RNA测序（RNA-Seq）分析还揭示了DKK3等参与免疫应答信号通路的基因的意外调控模式。与此一致的是，我们发现ΔNp63的表达水平与OSCC中增强的抗肿瘤免疫微环境呈正相关，且ΔNp63可通过DKK3/核因子κB（NF-κB）依赖通路促进巨噬细胞对肿瘤细胞的吞噬作用。
结论 本研究首次全面阐明了HPV阳性OSCC异质性预后相关的分子机制，为亟需的生物标志物开发与靶向治疗方案提供了理论依据。