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Anti-tumour immunity controlled through mRNA m6A methylation and YTHDF1 in dendritic cells

Author

Listed:
  • Dali Han

    (Beijing Institute of Genomics, Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Jun Liu

    (The University of Chicago
    The University of Chicago
    The University of Chicago)

  • Chuanyuan Chen

    (Beijing Institute of Genomics, Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Lihui Dong

    (School of Medicine, Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, THU-PKU Center for Life Sciences, Tsinghua University)

  • Yi Liu

    (School of Medicine, Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, THU-PKU Center for Life Sciences, Tsinghua University)

  • Renbao Chang

    (Beijing Institute of Genomics, Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Xiaona Huang

    (The Ludwig Center for Metastasis Research, University of Chicago)

  • Yuanyuan Liu

    (Nanjing Medical University)

  • Jianying Wang

    (Nanjing Medical University)

  • Urszula Dougherty

    (The University of Chicago)

  • Marc B. Bissonnette

    (The University of Chicago)

  • Bin Shen

    (Nanjing Medical University)

  • Ralph R. Weichselbaum

    (The Ludwig Center for Metastasis Research, University of Chicago)

  • Meng Michelle Xu

    (School of Medicine, Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, THU-PKU Center for Life Sciences, Tsinghua University)

  • Chuan He

    (The University of Chicago
    The University of Chicago
    The University of Chicago)

Abstract

There is growing evidence that tumour neoantigens have important roles in generating spontaneous antitumour immune responses and predicting clinical responses to immunotherapies1,2. Despite the presence of numerous neoantigens in patients, complete tumour elimination is rare, owing to failures in mounting a sufficient and lasting antitumour immune response3,4. Here we show that durable neoantigen-specific immunity is regulated by mRNA N6-methyadenosine (m6A) methylation through the m6A-binding protein YTHDF15. In contrast to wild-type mice, Ythdf1-deficient mice show an elevated antigen-specific CD8+ T cell antitumour response. Loss of YTHDF1 in classical dendritic cells enhanced the cross-presentation of tumour antigens and the cross-priming of CD8+ T cells in vivo. Mechanistically, transcripts encoding lysosomal proteases are marked by m6A and recognized by YTHDF1. Binding of YTHDF1 to these transcripts increases the translation of lysosomal cathepsins in dendritic cells, and inhibition of cathepsins markedly enhances cross-presentation of wild-type dendritic cells. Furthermore, the therapeutic efficacy of PD-L1 checkpoint blockade is enhanced in Ythdf1−/− mice, implicating YTHDF1 as a potential therapeutic target in anticancer immunotherapy.

Suggested Citation

  • Dali Han & Jun Liu & Chuanyuan Chen & Lihui Dong & Yi Liu & Renbao Chang & Xiaona Huang & Yuanyuan Liu & Jianying Wang & Urszula Dougherty & Marc B. Bissonnette & Bin Shen & Ralph R. Weichselbaum & Me, 2019. "Anti-tumour immunity controlled through mRNA m6A methylation and YTHDF1 in dendritic cells," Nature, Nature, vol. 566(7743), pages 270-274, February.
  • Handle: RePEc:nat:nature:v:566:y:2019:i:7743:d:10.1038_s41586-019-0916-x
    DOI: 10.1038/s41586-019-0916-x
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    Cited by:

    1. Haiyan Zhang & Xiaojing Luo & Wei Yang & Zhiying Wu & Zhicong Zhao & Xin Pei & Xue Zhang & Chonghao Chen & Josh Haipeng Lei & Qingxia Shi & Qi Zhao & Yanxing Chen & Wenwei Wu & Zhaolei Zeng & Huai-Qia, 2024. "YTHDF2 upregulation and subcellular localization dictate CD8 T cell polyfunctionality in anti-tumor immunity," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Wanzun Lin & Li Chen & Haojiong Zhang & Xianxin Qiu & Qingting Huang & Fangzhu Wan & Ziyu Le & Shikai Geng & Anlan Zhang & Sufang Qiu & Long Chen & Lin Kong & Jiade J. Lu, 2023. "Tumor-intrinsic YTHDF1 drives immune evasion and resistance to immune checkpoint inhibitors via promoting MHC-I degradation," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    3. Wen-Lan Yang & Weinan Qiu & Ting Zhang & Kai Xu & Zi-Juan Gu & Yu Zhou & Heng-Ji Xu & Zhong-Zhou Yang & Bin Shen & Yong-Liang Zhao & Qi Zhou & Ying Yang & Wei Li & Peng-Yuan Yang & Yun-Gui Yang, 2023. "Nsun2 coupling with RoRγt shapes the fate of Th17 cells and promotes colitis," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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