Targeting the LMP1‐ALIX axis in EBV + nasopharyngeal carcinoma inhibits immunosuppressive small extracellular vesicle secretion and boosts anti‐tumor immunity

作者：Fajian He, Yan Gong, Tao Gan, Jian‐Guo Zhang, Qiuji Wu, Yushuang Tan, Yajie Cheng, Chunsheng Wang, Jinru Yang, Linzhi Han, Zhihao Wang, Yanping Gao, Jingyi He, Rui Bai, Peikai Sun, Xiaoyan Yu, Yajuan Zhou, Conghua Xie · 发表于：癌症：英文版 · 年份：2024 · DOI：10.1002/cac2.12619 · 被引用次数：22 · 研究领域：Viral-associated cancers and disorders、interferon and immune responses、Extracellular vesicles in disease

Abstract Background Immunotherapy has revolutionized the therapeutical regimen for nasopharyngeal carcinoma (NPC), yet its response rate remains insufficient. Programmed death‐ligand 1 (PD‐L1) on small extracellular vesicles (sEVs) mediates local and peripheral immunosuppression in tumors, and the mechanism of PD‐L1 loading into these vesicles is garnering increasing attention. Latent membrane protein 1 (LMP1), a key viral oncoprotein expressed in Epstein‐Barr virus (EBV)‐positive NPC, contributes to remodeling the tumor microenvironment. However, the precise mechanisms by which LMP1 modulates tumor immunity in NPC remain unclear. Here, we aimed to investigate the roles and regulatory mechanisms of LMP1 and sEV PD‐L1 in NPC immune evasion. Methods We analyzed the impact of LMP1 on tumor‐infiltrating lymphocyte abundance in NPC tissues and humanized tumor‐bearing mouse models using multiplex immunofluorescence (mIF) and flow cytometry, respectively. Transmission electron microscopy and nanoparticle tracking analysis were employed to characterize sEVs. Immunoprecipitation‐mass spectrometry was utilized to identify proteins interacting with LMP1. The regulatory effects of sEVs on tumor microenvironment were assessed by monitoring CD8 + T cell proliferation and interferon‐γ (IFN‐γ) expression via flow cytometry. Furthermore, the expression patterns of LMP1 and downstream regulators in NPC were analyzed using mIF and survival analysis. Results High LMP1 expression in NPC patient s...