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.Furtherm...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.展开更多
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)+5 种基金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).
文摘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.
