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

By Dali Han, Jun Liu, Chuanyuan Chen, Lihui Dong, Yi Liu, Renbao Chang, Xiaona Huang, Yuanyuan Liu, Jianying Wang, U. Dougherty and 5 more. Nature, 2019

693 citations recorded by the source corpus.

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. The m6A reader protein YTHDF1 suppresses the clearance of tumour cells by enhancing the translation of lysosomal proteases in dendritic cells and thereby suppressing tumour antigen presentation.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/32943677ab3e89e180a44aedc1d9519ab512aeab

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In Molecular Biology

1. S. Zaccara
2. Samie R. Jaffrey
3. R. Su
4. Jianjun Chen
5. Huilin Huang
6. Xiaolan Deng
7. Hengyou Weng
8. Chuan He

In Oncology

1. Ravi Salgia
2. Samie R. Jaffrey

Citations in the corpus

• The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation (2020, background): “It is well-recognized that YTHDF1 acts as an m6A reader, YTHDF1 functions via binding and affecting m6A methylated transcripts (5,10,24,25).”
• A Unified Model for the Function of YTHDF Proteins in Regulating m6A-Modified mRNA (2020, background): “…their similar RNA-binding properties An important concept in m6A-mediated gene regulation is that the different DF proteins bind distinct subsets of m6A residues in the transcriptome (Han et al., 2019; Liu et al., 2018; Shi et al., 2017; Shi et al., 2019; Shi et al., 2018; Wang et al., 2015).”
• Targeting FTO suppresses cancer stem cell maintenance and immune evasion (2020, positive): “Different from previous studies showing the role of YTHDF1 (a m6A reader) in the cross-presentation of tumor antigens and the cross-priming of CD8+ T cells (Han et al., 2019) as well as the role of FTO in promoting melanoma tumorigenesis and anti-PD-1 resistance (Yang et al.”