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Anti-tumour immunity controlled through mRNA m~6A methylation and YTHDF1 in dendritic cells

机译：通过mRNA m〜6A甲基化和YTHDF1控制树突状细胞的抗肿瘤免疫力

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摘要

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.
机译：越来越多的证据表明，肿瘤新抗原在产生自发性抗肿瘤免疫反应和预测对免疫疗法的临床反应中具有重要作用（1,2）。尽管患者中存在许多新抗原，但由于未能建立足够而持久的抗肿瘤免疫反应而无法完全消除肿瘤（3,4）。在这里，我们显示持久性新抗原特异性免疫受到通过m（6）A结合蛋白YTHDF1（5）的mRNA N-6-甲基腺苷（m（6）A）甲基化的调节。与野生型小鼠相比，Ythdf1缺陷型小鼠显示出更高的抗原特异性CD8（+）T细胞抗肿瘤反应。 YTHDF1在经典树突状细胞中的丢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物由m（6）A标记并由YTHDF1识别。 YTHDF1绑定到这些成绩单增加树突状细胞中的溶酶体组织蛋白酶的翻译，和组织蛋白酶的抑制作用显着增强了野生型树突状细胞的交叉展示。此外，PD-L1检查点封锁的治疗功效在Ythdf1（-/-）小鼠中得到增强，这暗示YTHDF1作为抗癌免疫疗法中的潜在治疗靶标。

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  • 来源
    《Nature》 |2019年第7743期|270-274|共5页
  • 作者

    Han Dali; Liu Jun; Chen Chuanyuan; Dong Lihui; Liu Yi; Chang Renbao; Huang Xiaona; Liu Yuanyuan; Wang Jianying; Dougherty Urszula; Bissonnette Marc B.; Shen Bin; Weichselbaum Ralph R.; Xu Meng Michelle; He Chuan;

  • 作者单位

    Tsinghua Univ, Beijing Key Lab Immunol Res Chron Dis, THU PKU Ctr Life Sci, Dept Basic Med Sci,Sch Med,Inst Immunol, Beijing, Peoples R China;

    Chinese Acad Sci, Beijing Inst Genom, Key Lab Genom & Precis Med, Beijing, Peoples R China;

    Nanjing Med Univ, Dept Histol & Embryol, State Key Lab Reprod Med, Nanjing, Jiangsu, Peoples R China;

    Chinese Acad Sci, Inst Stem Cell & Regenerat, Beijing, Peoples R China;

    Univ Chicago, Dept Biochem & Mol Biol, 920 E 58Th St, Chicago, IL 60637 USA;

    Univ Chicago, Howard Hughes Med Inst, Inst Biophys Dynam, 5841 S Maryland Ave, Chicago, IL 60637 USA;

    Univ Chicago, Dept Radiat & Cellular Oncol, Ludwig Ctr Metastasis Res, Chicago, IL 60637 USA;

    Univ Chinese Acad Sci, Coll Future Technol, Sino Danish Coll, Beijing, Peoples R China;

    Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA;

    Univ Chicago, Dept Chem, 5735 S Ellis Ave, Chicago, IL 60637 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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