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Nature. 2019 Feb;566(7743):270-274. doi: 10.1038/s41586-019-0916-x. Epub 2019 Feb 6.

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

Han D1,2,3, Liu J4,5,6, Chen C7,8,9, Dong L10, Liu Y10, Chang R7,8, Huang X11, Liu Y12, Wang J12, Dougherty U13, Bissonnette MB13, Shen B12, Weichselbaum RR11, Xu MM14, He C15,16,17.

Author information

1
Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China. handl@big.ac.cn.
2
Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China. handl@big.ac.cn.
3
College of Future Technology, Sino-Danish College, University of Chinese Academy of Sciences, Beijing, China. handl@big.ac.cn.
4
Department of Chemistry, The University of Chicago, Chicago, IL, USA.
5
Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA.
6
Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, Chicago, IL, USA.
7
Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
8
Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
9
College of Future Technology, Sino-Danish College, University of Chinese Academy of Sciences, Beijing, China.
10
Department of Basic Medical Sciences, School of Medicine, Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, THU-PKU Center for Life Sciences, Tsinghua University, Beijing, China.
11
Department of Radiation and Cellular Oncology, The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL, USA.
12
State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
13
Department of Medicine, The University of Chicago, Chicago, IL, USA.
14
Department of Basic Medical Sciences, School of Medicine, Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, THU-PKU Center for Life Sciences, Tsinghua University, Beijing, China. michellexu@mail.tsinghua.edu.cn.
15
Department of Chemistry, The University of Chicago, Chicago, IL, USA. chuanhe@uchicago.edu.
16
Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA. chuanhe@uchicago.edu.
17
Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, Chicago, IL, USA. chuanhe@uchicago.edu.

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.

PMID:
30728504
DOI:
10.1038/s41586-019-0916-x

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