Anti-tumour immunity controlled through mRNA m6A methylation and YTHDF1 in dendritic cells
Open accessAbstract
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 N 6-methyadenosine (m 6 A) methylation through the m 6 A-binding protein YTHDF1 5. 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 m 6 A 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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- Authors
- Han, D., Liu, J., Chen, C., Dong, L., Liu, Y., Chang, R., Huang, X., Liu, Y., Wang, J., Dougherty, U., Bissonnette, M. B., Shen, B., Weichselbaum, R. R., Xu, M. M., & He, C.
- Affiliations
- Chinese Academy of Sciences (CN)
- Howard Hughes Medical Institute (US)
- Peking University (CN)
- University of Chicago (US)
- State Key Laboratory of Reproductive Medicine (CN)
- Corresponding author
- Han, Dali
- Xu, Meng Michelle
- He, Chuan
- ORCID
- Venue
- Nature
- Published
- 2019-02
- Volume
- 566
- Issue
- 7743
- Pages
- 270-274
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6522227
- OpenAlex
- W2911349862
- Cited by
- 955
- References
- 40
- Citations by year
- 2026: 68 · 2025: 84 · 2024: 116 · 2023: 152 · 2022: 221 · 2021: 195 · 2020: 90 · 2019: 29
- FWCI
- 53.68
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-03-25)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Human Genome Research Institute (RM1HG008935)
- National Cancer Institute (U01CA217078)
- National Institute of General Medical Sciences (R01GM113194)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- YTHDF1, dendritic cells, neoantigens, antitumor immunity, cross-presentation, cathepsins, lysosomal proteases, translational regulation, PD-L1 blockade, cancer immunotherapy, tumor antigen presentation
- MeSH terms
- Adenosine, Animals, Antigens, Neoplasm, Binding Sites, Cathepsins, Dendritic Cells, Female, Humans, Methylation, Mice, Inbred C57BL, Neoplasms, Proteins, RNA, Messenger, Protein Biosynthesis, RNA-Binding Proteins, Antigen Presentation, CD8-Positive T-Lymphocytes, Cross-Priming, Mice, Transcriptome, B7-H1 Antigen
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