Department of Otolaryngology-Head and Neck Surgery, Xiamen Medical College Affiliated Haicang Hospital, The Sixth Hospital of Xiamen City, The Haicang Hospital of Xiamen, Xiamen, China.
Department of Oncology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, China.
Front Immunol. 2024 Aug 21;15:1445472. doi: 10.3389/fimmu.2024.1445472. eCollection 2024.
Most head and neck squamous cell carcinoma (HNSCC) patients are diagnosed at an advanced local stage. While immunotherapy has improved survival rates, only a minority of patients respond durably to targeted immunotherapies, posing substantial clinical challenges. We investigated the heterogeneity of the tumor microenvironment in HNSCC cohorts before and after immunotherapy by analyzing single-cell RNA sequencing (scRNA-seq) data and bulk RNA sequencing datasets retrieved from public databases.
We constructed a single-cell transcriptome landscape of HNSCC patients before and after immunotherapy and analyzed the cellular composition, developmental trajectories, gene regulatory networks, and communication patterns of different cell type subpopulations. Additionally, we assessed the expression levels of relevant indicators in HNSCC cells via western blot, ELISA, and fluorescent probe techniques.
At the single-cell level, we identified a subpopulation of TP63 SLC7A5 HNSCC that exhibited a ferroptosis-resistant phenotype. This subpopulation suppresses ferroptosis in malignant cells through the transcriptional upregulation of SLC7A5 mediated by high TP63 expression, thereby promoting tumor growth and resistance to immunotherapy. The experimental results demonstrated that the overexpression of TP63 upregulated the expression of SLC7A5 and suppressed the concentrations of Fe and ROS in HNSCC cells. By integrating bulk transcriptome data, we developed a clinical scoring model based on TP63 and SLC7A5, which are closely associated with tumor stage, revealing the significant prognostic efficacy of the TP63 SLC7A5 HNSCC-mediated ferroptosis mechanism in HNSCC patients.
Our research elucidates the TME in HNSCC before and after immunotherapy, revealing a novel mechanism by which TP63 SLC7A5 HNSCC inhibits ferroptosis and enhances tumor resistance via TP63-induced SLC7A5 upregulation. These insights lay the foundation for the development of more effective treatments for HNSCC.
大多数头颈部鳞状细胞癌（HNSCC）患者在局部晚期被诊断出来。虽然免疫疗法提高了生存率，但只有少数患者能持久地对靶向免疫疗法产生反应，这给临床带来了巨大挑战。我们通过分析从公共数据库中检索到的单细胞 RNA 测序（scRNA-seq）数据和批量 RNA 测序数据集，研究了 HNSCC 患者免疫治疗前后肿瘤微环境的异质性。
我们构建了 HNSCC 患者免疫治疗前后的单细胞转录组图谱，并分析了不同细胞亚群的细胞组成、发育轨迹、基因调控网络和通信模式。此外，我们还通过 Western blot、ELISA 和荧光探针技术评估了 HNSCC 细胞中相关指标的表达水平。
在单细胞水平上，我们鉴定出了一个具有铁死亡抗性表型的 TP63 SLC7A5 HNSCC 亚群。该亚群通过高表达的 TP63 介导的 SLC7A5 的转录上调抑制恶性细胞中的铁死亡，从而促进肿瘤生长和对免疫治疗的抵抗。实验结果表明，TP63 的过表达上调了 SLC7A5 的表达，并降低了 HNSCC 细胞中的 Fe 和 ROS 浓度。通过整合批量转录组数据，我们开发了一种基于与肿瘤分期密切相关的 TP63 和 SLC7A5 的临床评分模型，揭示了 TP63 SLC7A5 HNSCC 介导的铁死亡机制在 HNSCC 患者中的显著预后疗效。
我们的研究阐明了 HNSCC 免疫治疗前后的 TME，揭示了 TP63 SLC7A5 HNSCC 通过 TP63 诱导的 SLC7A5 上调抑制铁死亡并增强肿瘤耐药性的新机制。这些发现为开发更有效的 HNSCC 治疗方法奠定了基础。
