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

Abstract

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.

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Data availability

Raw SMART-seq, RNA-seq, HiC-seq, and scRNA-seq data were deposited in NCBI under the accession numbers GSE242164, GSE234457, GSE239507, and GSE263391, respectively. All the data from this study have been included in the manuscript and Supplemental Information.

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Acknowledgements

This work was 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) and 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).

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Author notes

  1. These authors contributed equally: Shuai Wang, Lijun Meng, Nan Xu, Huan Chen, Zhaofeng Xiao.

Authors and Affiliations

  1. Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou First People’s Hospital, Hangzhou, 310006, China

    Shuai Wang, Lijun Meng & Xuyong Wei

  2. Zhejiang University School of Medicine, Hangzhou, 310000, Zhejiang, China

    Nan Xu

  3. The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China

    Huan Chen & Zhaofeng Xiao

  4. School of Clinical Medicine, Hangzhou Medical College, Hangzhou, 310059, Zhejiang, China

    Di Lu, Qiang Wei & Xiao Xu

  5. NHC Key Laboratory of Combined Multi-Organ Transplantation Hangzhou China, Hangzhou, China

    Di Lu, Jun Chen, Shusen Zheng, Qiang Wei & Xiao Xu

  6. National Key Laboratory of Chinese Medicine Modernization, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing, 314103, China

    Xiaohui Fan

  7. State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, 710032, China

    Limin Xia

  8. Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, 310000, China

    Jun Chen

  9. Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, 310000, Zhejiang, China

    Shusen Zheng

  10. Institute of Translational Medicine, Zhejiang University, 310000, Hangzhou, China

    Xiao Xu

Authors

  1. Shuai Wang
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  2. Lijun Meng
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  13. Xiao Xu
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Contributions

Conception and design: X.X., X.Y.W. and S.W. Development of Methodology, S.W., L.J.M. and N.X. Data Acquisition, S.W., L.J.M., N.X., H.C. and Z.F.X. Data Analysis & Interpretation, S.W., L.J.M., N.X., H.C. and Z.F.X. Writing, reviewing, and revising the manuscript: S.W., L.J.M., N.X., H.C., Z.F.X., D.L., X.H.F., L.M.X., and J.C. Administrative, Technical, and Material Support, S.X.Z., and Q.W. Study Supervision, X.X. and X.Y.W.

Corresponding authors

Correspondence to
Shuai Wang, Xuyong Wei or Xiao Xu.

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The authors declare no competing interests.

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Wang, S., Meng, L., Xu, N. et al. Hepatocellular carcinoma-specific epigenetic checkpoints bidirectionally regulate the antitumor immunity of CD4 + T cells.
Cell Mol Immunol (2024). https://doi.org/10.1038/s41423-024-01215-0

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  • Received: 20 March 2024

  • Accepted: 03 September 2024

  • Published: 19 September 2024

  • DOI: https://doi.org/10.1038/s41423-024-01215-0

Keywords

  • MATR3
  • Tconv
  • ARID1A
  • TOX
  • Exhaustion

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