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

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

Dali Han ¹ ² ³, Jun Liu ⁴ ⁵ ⁶, Chuanyuan Chen ⁷ ⁸ ⁹, Lihui Dong ¹⁰, Yi Liu ¹⁰, Renbao Chang ⁷ ⁸, Xiaona Huang ¹¹, Yuanyuan Liu ¹², Jianying Wang ¹², Urszula Dougherty ¹³, Marc B Bissonnette ¹³, Bin Shen ¹², Ralph R Weichselbaum ¹¹, Meng Michelle Xu ¹⁴, Chuan He ¹⁵ ¹⁶ ¹⁷

Affiliations

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.

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

Abstract

There is growing evidence that tumour neoantigens have important roles in generating spontaneous antitumour immune responses and predicting clinical responses to immunotherapies^1,2. Despite the presence of numerous neoantigens in patients, complete tumour elimination is rare, owing to failures in mounting a sufficient and lasting antitumour immune response^3,4. 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.

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