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

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, Meng Michelle Xu () and Chuan He ()
Additional contact information
Dali Han: Beijing Institute of Genomics, Chinese Academy of Sciences
Jun Liu: The University of Chicago
Chuanyuan Chen: Beijing Institute of Genomics, 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
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

Nature, 2019, vol. 566, issue 7743, 270-274

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-0916-x

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