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 Gan Tao Jianguo 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 

机构地区：[1]Department of Radiation and Medical Oncology,Hubei Key Laboratory of Tumor Biological Behaviors,Hubei Cancer Clinical Study Center,Zhongnan Hospital of Wuhan University,Wuhan,Hubei,P.R.China [2]Tumor Precision Diagnosis and Treatment Technology and Translational Medicine,Hubei Engineering Research Center,Zhongnan Hospital of Wuhan University,Wuhan,Hubei,P.R.China [3]Department of Radiotherapy,Hubei Cancer Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,Hubei,P.R.China [4]Wuhan Research Center for Infectious Diseases and Cancer,Chinese Academy of Medical Sciences,Wuhan,Hubei,P.R.China

出　　处：《Cancer Communications》2024年第12期1391-1413,共23页癌症通讯(英文)

基　　金：Health Commission of Hubei Province Medical Leading Talent Project,and Translational Medicine and Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University,Grant/Award Numbers:ZNJC201922,ZNJC202007;Key Research&Development Project of Hubei Province,Grant/Award Number:2020BCA069;National Natural Science Foundation of China,Grant/Award Numbers:81803065,81972852;Research Projects of Biomedical Center of Hubei Cancer Hospital,Grant/Award Number:2022SWZX12。

摘　　要：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 specimens and mouse models was associated with restricted infiltration of CD8^(+)T cells.Additionally,LMP1 promoted sEV PD-L1 secretion,leading to inhibition of CD8^(+)T cell viability and IFN-γ expression in vitro.Mechanistically,LMP1 recruited apoptosis-linked gene 2-interacting protein X(ALIX)through its intracellular domain and bound PD-L1 through its transmembrane domain,thereby facilitating the loading of PDL1 into ALIX-dependent sEVs.Disruption of ALIX diminished LMP1-induced sEV PD-L1 secretion and enhanced the anti-tumor immunity of CD8^(+)T cells both in vitro and in

关 键 词：Epstein-Barr virus latent membrane protein 1 small extracellular vesicle PD-L1 ALIX nasopharyngeal carcinoma 

分 类 号：R73[医药卫生—肿瘤]