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

Abstract

Emerging evidence revealed important roles of tumor neoantigens in generating spontaneous antitumor immune responses and predicting clinical responses to immunotherapies1,2. Despite the presence of numerous neoantigens, complete tumor elimination rarely occurs in many patients, due to failures in mounting a sufficient and lasting antitumor immune response3,4. Here, we show that durable neoantigen-specific immunity is regulated by messenger RNA (mRNA) N6-methyadenosine (m6A) methylation through the m6A-binding protein YTHDF15. In contrast to wild-type mice, Ythdf1-deficient (Ythdf1−/−) mice exhibit an elevated antigen-specific CD8+ T cell antitumor response. Loss of YTHDF1 in classical dendritic cells (cDCs) enhanced the cross-presentation of tumor antigen 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 elevates translation of lysosomal cathepsins in DCs, with the inhibition of cathepsins markedly enhancing cross-presentation of the wild-type DCs. Furthermore, the therapeutic efficacy of PD-L1 checkpoint blockade is enhanced in Ythdf1−/− mice, implicating YTHDF1 as a new potential therapeutic target in anticancer immunotherapy.