The m⁶A-Binding Protein YTHDF1 Mediates Immune Evasion

Effective antitumor immunity is dependent on sufficient priming of T cells against tumor neoantigens. However, the mechanisms by which tumors evade neoantigen recognition remain incompletely understood. Han, Liu, and colleagues found that loss of YTHDF1, a protein that increases mRNA translation efficiency via binding to N⁶-methyladenosine (m⁶A) post-transcriptional modifications in mRNA, attenuated tumor growth in mice. This antitumor effect was mediated by increased T-cell priming against tumor neoantigens and an enhanced antigen-specific CD8⁺ T-cell response. Deletion of Ythdf1 specifically in classic dendritic cells (DC) augmented the ability of these cells to cross-prime CD8⁺ T cells compared with wild-type DCs and was sufficient to inhibit tumor growth, suggesting that recognition of mRNA m⁶A methylation by YTHDF1 restricts the capacity of DCs to present internalized tumor neoantigens to T cells. Consistent with this idea, YTHDF1-bound mRNAs in DCs were enriched in m⁶A-marked transcripts encoding lysosomal cathepsin proteases, which have been shown to promote antigen degradation in DCs, and loss of Ythdf1 reduced the translational efficiency of multiple cathepsin transcripts in classic DCs. Inhibition of lysosomal cathepsins increased the cross-priming of CD8⁺ T cells by wild-type DCs and enhanced the antitumor response in wild-type mice, supporting the notion that YTHDF1 limits immune recognition by promoting the expression of lysosomal proteases that degrade neoantigens in DCs. Furthermore, the increased neoantigen-specific CD8⁺ T-cell response in Ythdf1-deficient mice enhanced the antitumor efficacy of anti–PD-L1 antibody, resulting in complete tumor regressions. These findings identify YTHDF1 as a key mediator of tumor immune evasion and a potential therapeutic target to improve the clinical response to immune checkpoint blockade.

Han D, Liu J, Chen C, Dong L, Liu Y, Chang R, et al. Anti-tumour immunity controlled through mRNA m⁶A methylation and YTHDF1 in dendritic cells. Nature 2019;566:270–4.

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