Hepatocellular carcinoma-specific epigenetic checkpoints bidirectionally regulate the antitumor immunity of CD4+T cells  

作　　者：Shuai Wang Lijun Meng Nan Xu Huan Chen Zhaofeng Xiao Di Lu Xiaohui Fan Limin Xia Jun Chen Shusen Zheng Qiang Wei Xuyong Wei Xiao Xu 

机构地区：[1]Key Laboratory ofintegrated Oncology and Inteligent Medicine of Zhejang Province,Hangzhou First People's Hospital,Hangzhou 310006,China [2]Zhejiang University School of Medicine,Hangzhou 310ooo Zhejiang,China [3]The Fourth School of Clinical Medicine,Zhejiang Chinese Medical University,Hangzhou,China [4]School of Clinical Medicine,Hangzhou Medical College,Hangzhou 310059 Zhejiang,China [5]NHC Key Laboratory of Combined Multi-Organ Transplantation Hangzhou China,Hangzhou,China [6]National Key Laboratory of Chinese Medicine Modernization,Innovation Center of Yangtze River Delta,Zhejiang University,Jiaxing 314103,China [7]State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Centerfor Digestive Diseases,Xijing Hospital of Digestive Diseases,Fourth Military Medical University,Xian 710032,China [8]Department of Hepatobiliary&Pancreatic Surgery and Minimally Invasive Surgery,Zhejiang Provincial People's Hospital(Affliated People's Hospital),Hangzhou Medical College,Hangzhou,Zhejiang 310ooo,China [9]shulan(Hangzhou)Hospital Affliated to Zhejiang Shuren University Shulan International Medical College,Hangzhou 310000 Zhejang,China [10]Institute of Translational Medicine,Zhejiang University,310000 Hangzhou,China

出　　处：《Cellular & Molecular Immunology》2024年第11期1296-1308,共13页中国免疫学杂志(英文版)

基　　金：supported by the Key Program,National Natural Science Foundation of China(No.81930016);National Key Research and Development Program of China(No.2021YFA1100500);Key Research&Development Plan of Zhejiang Province(No.2019C03050);Construction Fund of Key Medical Disciplines of Hangzhou(OO20200093);Key Research&Development Plan of Zhejiang Province(No.2021C03118),Projects of Medical and Health Technology Program in Zhejiang Province(WKJ-ZJ-2120);National Natural Science Foundation of China(No.82273177,No.12304256);Natural Science Foundation of Zhejiang Province(LY22H160046,LQ24C050005);Key Research and Development Plan of Zhejiang Province(2022C03108).Joint Funds of the National Natural Science Foundation of China(No.U23A20451).

摘　　要：Hepatocellular carcinoma(HCC)is a highly malignant tumor with significant global health implications.The role of CD4+T cells,particularly conventional CD4+T cells(Tconvs),in HCC progression remains unexplored.Furthermore,epigenetic factors are crucial in immune regulation,yet their specific role in HCC-infiltrating Tconv cells remains elusive.This study elucidates the role of MATR3,an epigenetic regulator,in modulating Tconv activity and immune evasion within the HCC microenvironment.Reanalysis of the scRNA-seq data revealed that early activation of CD4+T cells is crucial for establishing an antitumor immune response.In vivo and in vitro experiments revealed that Tconv enhances cDC1-induced CD8+T-cell activation.Screening identified MATR3 as a critical regulator of Tconv function,which is necessary for antitumour activity but harmful when overexpressed.Excessive MATR3 expression exacerbates Tconv exhaustion and impairs function by recruiting the SWI/SNF complex to relax chromatin in the TOX promoter region,leading to aberrant transcriptional changes.In summary,MATR3 is an HCC-specific epigenetic checkpoint that bidirectionally regulates Tconv antitumour immunity,suggesting new therapeutic strategies targeting epigenetic regulators to enhance antitumour immunity in HCC.

关 键 词：MATR3 Tconv ARID1A TOX EXHAUSTION 

分 类 号：R73[医药卫生—肿瘤]