EBV阳性鼻咽癌来源的细胞外囊泡相关LMP1诱导LIF介导的免疫抑制性巨噬细胞极化并损害抗肿瘤免疫
Extracellular vesicle-associated LMP1 from EBV-positive nasopharyngeal carcinoma induces LIF-mediated immunosuppressive macrophage polarization and impairs anti-tumor immunity.
文献信息
| PMID | 42874988 |
|---|---|
| 原文 | 在 PubMed 查看原文 ↗ |
| 发表日期 | 2026 |
| 作者 | Tzu-Tung Liu |
| 作者单位 | Department of Biomedical Sciences and Engineering, National Central University, 300, Zhongda Rd., Jhongli Dist., Taoyuan City 32001, Taiwan; National Institute of Cancer Research, National Health Research Institutes, 35 Keyan Rd., Zhunan, 35053 Miaoli County, Taiwan. |
| 期刊 | Cancer letters |
| SCI 分区 | Q1 |
| IF | 10.8 |
| 研究类型 | 基础研究 · 基础／转化 |
| 所属专科 | 鼻咽癌 |
中文摘要
背景： EB病毒（EBV）相关鼻咽癌（NPC）的特征是高度浸润但免疫抑制的肿瘤微环境（TME），其中肿瘤相关巨噬细胞（TAMs）促进疾病进展。方法：在此，我们鉴定了一条由细胞外囊泡（EV）介导的LMP1-NF-κB-LIF信号轴，该轴促进NPC中的巨噬细胞重编程和免疫抑制。单细胞转录组分析显示，EV暴露诱导肿瘤和免疫细胞群体的转录重塑，并伴随髓系区室中TAM比例增加。NPC来源的EV被巨噬细胞摄取，其中EV相关LMP1诱导NF-κB激活、LIF表达以及向免疫抑制表型的极化。功能丧失和功能获得研究，连同LMP1 CTAR1/CTAR2结构域的结构-功能分析，进一步支持这些CTAR结构域对于有效NF-κB激活和LIF诱导的必要性。结果：在功能上，EV教育的巨噬细胞表现出受损的吞噬活性，并促进抑制性T细胞反应。在斑马鱼、3D球体和小鼠异种移植模型中，EV教育的巨噬细胞促进NPC生长和血管播散，而用可溶性LIFR阻断LIF信号可减弱这些效应。肿瘤LIF表达与CTLA4表达呈正相关。在NPC组织中，LIF表达优先与基质巨噬细胞相关，且基质LIF表达升高与转移、晚期淋巴结疾病和晚期临床分期相关。基质免疫细胞LMP1表达也与LIF表达相关，并且在发生转移的患者中更高。结论：总体而言，这些发现支持一条EV相关LMP1-NF-κB-LIF轴，该轴将EBV阳性NPC细胞与巨噬细胞介导的免疫抑制和肿瘤进展联系起来，并为进一步研究该通路作为潜在治疗靶点提供了基础。
英文摘要
Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is characterized by a highly infiltrated yet immunosuppressive tumor microenvironment (TME), in which tumor-associated macrophages (TAMs) contribute to disease progression. Here, we identify an extracellular vesicle (EV)-mediated LMP1-NF-κB-LIF signaling axis that promotes macrophage reprogramming and immune suppression in NPC. Single-cell transcriptomic analysis revealed that EV exposure induces transcriptional remodeling across tumor and immune-cell populations, accompanied by an increased proportion of TAMs within the myeloid compartment. NPC-derived EVs were taken up by macrophages, where EV-associated LMP1 induced NF-κB activation, LIF expression, and polarization toward an immunosuppressive phenotype. Loss- and gain-of-function studies, together with structure-function analyses of the LMP1 CTAR1/CTAR2 domains, further supported the requirement of these CTAR domains for efficient NF-κB activation and LIF induction. Functionally, EV-educated macrophages exhibited impaired phagocytic activity and promoted inhibitory T-cell responses. In zebrafish, 3D spheroid, and mouse xenograft models, EV-educated macrophages promoted NPC growth and vascular dissemination, whereas blockade of LIF signaling with soluble LIFR attenuated these effects. Tumor LIF expression positively correlated with CTLA4 expression. In NPC tissues, LIF expression was preferentially associated with stromal macrophages, and elevated stromal LIF expression was associated with metastasis, advanced nodal disease, and advanced clinical stage. Stromal immune-cell LMP1 expression also correlated with LIF expression and was higher in patients who developed metastasis. Collectively, these findings support an EV-associated LMP1-NF-κB-LIF axis that links EBV-positive NPC cells to macrophage-mediated immune suppression and tumor progression and provide a basis for further investigating this pathway as a potential therapeutic target.