RNA m6A-Ythdf1 in dendritic cells triggers anti-tumor immunity (ribo-seq and m6a-seq in GMDCs)

Emerging evidence emphasizes the important role of tumor neoantigen in generating the spontaneous antitumor immune response and predicting the clinical response to immunotherapies. Despite the presence of numerous neoantigens, complete tumor elimination rarely occurs in majority of patients due to failures in mounting a sufficient and lasting antitumor immunity. Here we show that the durable neoanitgen-specific immunity is regulated by a m6A-binding protein, Ythdf1. In contrast to wild-type mice, Ythdf1-deficient (Ythdf1-/-) mice generate more antigen-specific CD8+ T cell response for persistent tumor control. Loss of Ythdf1 in dendritic cell (DC) results in an enhanced cross-presentation of tumor antigen and cross-priming of CD8+ T cell in vivo. To confirm our observations, we performed Ribo-Seq to analyze the translational efficiency of genes in DCs and performed m6A-seq to locate the m6A sites.

越来越多的研究证据表明，肿瘤新抗原（tumor neoantigen）在诱导自发性抗肿瘤免疫应答以及预测免疫治疗临床响应方面发挥着关键作用。尽管多数患者体内存在大量新抗原，但由于无法启动充足且持久的抗肿瘤免疫应答，绝大多数患者难以实现肿瘤的完全清除。本研究发现，持久的新抗原特异性免疫受m6A结合蛋白（m6A-binding protein）Ythdf1调控。与野生型小鼠相比，Ythdf1敲除（Ythdf1-/-）小鼠可产生更强的抗原特异性CD8+ T细胞应答，进而实现持久的肿瘤控制。树突状细胞（dendritic cell, DC）中Ythdf1的缺失，可在体内增强肿瘤抗原的交叉呈递效应与CD8+ T细胞的交叉致敏作用。为验证上述实验结果，本研究通过核糖体测序（Ribo-Seq）分析树突状细胞内的基因翻译效率，并借助m6A测序（m6A-seq）定位m6A修饰位点。