Anti-tumour immunity controlled through mRNA m6A methylation and YTHDF1 in dendritic cells
Anti-tumour immunity controlled through mRNA m6A methylation and YTHDF1 in dendritic cells
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树突状细胞中通过 mRNA m6A 甲基化和 YTHDF1 控制的抗肿瘤免疫
DOI：
10.1038/s41586-019-0916-x
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发表时间：
2019-02-14
期刊：
影响因子：
64.8
通讯作者：
He, Chuan
中科院分区：
文献类型：
--
作者：
Han, Dali;Liu, Jun;He, Chuan
越来越多的证据表明，肿瘤新抗原在产生自发抗肿瘤免疫反应和预测免疫疗法的临床反应方面具有重要作用(1,2)。尽管患者体内存在大量新抗原，但由于未能建立足够且持久的抗肿瘤免疫反应，完全消除肿瘤的情况很少见(3,4)。在这里，我们表明持久的新抗原特异性免疫是通过 m(6)A 结合蛋白 YTHDF1(5) 受 mRNA N-6-甲基腺苷 (m(6)A) 甲基化调节的。与野生型小鼠相比，Ythdf1缺陷型小鼠表现出更高的抗原特异性CD8(+) T细胞抗肿瘤反应。经典树突状细胞中YTHDF1的缺失增强了体内肿瘤抗原的交叉呈递和CD8+T细胞的交叉引发。从机制上讲，编码溶酶体蛋白酶的转录本由 m(6)A 标记并由 YTHDF1 识别。 YTHDF1 与这些转录物的结合增加了树突状细胞中溶酶体组织蛋白酶的翻译，并且组织蛋白酶的抑制显着增强了野生型树突状细胞的交叉呈递。此外，PD-L1检查点阻断的治疗效果在Ythdf1(-/-)小鼠中得到增强，这表明YTHDF1作为抗癌免疫疗法的潜在治疗靶点。
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.