乙醛脱氢酶2通过CXCR4-CXCL12信号重塑头颈部鳞状细胞癌的肿瘤免疫微环境
Acetaldehyde Dehydrogenase 2 Remodels the Tumor Immune Microenvironment via CXCR4-CXCL12 Signaling in Head and Neck Squamous Cell Carcinoma.
文献信息
| PMID | 42906687 |
|---|---|
| 原文 | 在 PubMed 查看原文 ↗ |
| 发表日期 | 2026 |
| 作者 | Taowei Wu |
| 作者单位 | Department of Otolaryngology-Head and Neck Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangzhou, China. |
| 期刊 | The Journal of biological chemistry |
| SCI 分区 | Q2 |
| IF | 4.5 |
| 研究类型 | 基础研究 · 基础／转化 |
| 所属专科 | 耳科 |
中文摘要
免疫检查点阻断（ICB）改善了复发/转移性头颈部鳞状细胞癌（R/M HNSCC）患者的结局，但仅少数患者获得持久的治疗获益。乙醛脱氢酶2（ALDH2）上调与有利的ICB反应相关，但其免疫代谢机制仍未完全阐明。利用单中心喉鳞状细胞癌（LSCC）队列和多个接受ICB治疗的HNSCC队列，我们仅从LSCC样本中推导空间生物标志物截断值，并前瞻性地将其应用于混合HNSCC队列，以研究ALDH2相关的肿瘤微环境（TME）改变并构建免疫治疗反应空间特征。对TCGA-HNSCC的生物信息学分析显示，ALDH2与CD8+ T细胞浸润呈正相关。采用HALO空间定量的多重免疫荧光（mIF）显示，在同一肿瘤区域内，ALDH2+肿瘤细胞与CD8+ T淋巴细胞的定位显著更近。体外共培养显示，ALDH2过表达提高CD8+ T细胞比例和IFNγ水平。转录组和细胞功能实验确定CXCL12是介导ALDH2相关T细胞聚集的候选趋化因子。我们基于三个独立多中心队列的肿瘤-免疫邻近度指标构建并外部验证了ALDH2-CD8+ T空间预测特征。在LSCC患者中，较短的ALDH2-CD8距离与延长的无进展生存期（PFS）和总生存期（OS）相关，而按ALDH2+肿瘤细胞密度分层则带来显著的PFS获益，但OS趋势不显著。多中心检测验证了该空间特征对ICB反应的预测能力。我们的数据支持ALDH2过表达、CXCL12升高与CXCR4依赖性CD8+ T细胞迁移之间的体外关联；ALDH2驱动CXCL12上调的上游机制及体内功能结局仍未阐明。
英文摘要
Immune checkpoint blockade (ICB) improves outcomes for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), yet only a minority of patients achieve durable therapeutic benefits. Upregulated acetaldehyde dehydrogenase 2 (ALDH2) correlates with favorable ICB responses, though its immune-metabolic mechanisms remain incompletely characterized. Using a single-center laryngeal squamous cell carcinoma (LSCC) cohort and multiple ICB-treated HNSCC cohorts, we derived spatial-biomarker cut-offs exclusively from LSCC samples, which were prospectively applied to mixed HNSCC cohorts to investigate ALDH2-linked tumor microenvironment (TME) alterations and build an immunotherapy-response spatial signature. Bioinformatic analysis of TCGA-HNSCC revealed ALDH2 positively correlated with CD8+ T cell infiltration. Multiplex immunofluorescence (mIF) with HALO spatial quantification demonstrated that ALDH2+ tumor cells localize significantly closer to CD8+ T lymphocytes within identical tumor regions. In vitro co-cultures showed ALDH2 overexpression elevates CD8+ T cell proportions and IFNγ levels. Transcriptome and cellular functional assays identified CXCL12 as a candidate chemokine mediating ALDH2-related T cell accumulation. We constructed and externally validated an ALDH2-CD8+ T spatial predictive signature based on tumor-immune proximity metrics across three independent multicenter cohorts. Among LSCC patients, shorter ALDH2-CD8 distances correlated with prolonged progression-free survival (PFS) and overall survival (OS), whereas stratification by ALDH2+ tumor cell density yielded significant PFS benefit but only a non-significant OS trend. Multicenter testing validated this spatial signature's predictive capacity for ICB response. Our data support an in vitro association among ALDH2 overexpression, elevated CXCL12, and CXCR4 dependent CD8+ T cell migration; the upstream mechanism for ALDH2-driven CXCL12 upregulation and in vivo functional outcomes remain uncharacterized.