Methionine deficiency facilitates antitumour immunity by altering m(6)A methylation of immune checkpoint transcripts.
Methionine deficiency facilitates antitumour immunity by altering m(6)A methylation of immune checkpoint transcripts.
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蛋氨酸缺乏通过改变免疫检查点转录本的 m6A 甲基化来促进抗肿瘤免疫
DOI：
10.1136/gutjnl-2022-326928
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发表时间：
2023-03
期刊：
影响因子：
24.5
通讯作者：
Ju, Huai-Qiang
中科院分区：
文献类型：
--
作者：
Li, Ting;Tan, Yue-Tao;Chen, Yan-Xing;Zheng, Xiao-Jun;Wang, Wen;Liao, Kun;Mo, Hai-Yu;Lin, Junzhong;Yang, Wei;Piao, Hai-Long;Xu, Rui-Hua;Ju, Huai-Qiang
甲硫氨酸代谢涉及无数的细胞功能，包括甲基化反应和氧化还原维持。然而，目前还不清楚蛋氨酸代谢，RNA甲基化和抗肿瘤免疫是否在分子上交织在一起。在小鼠模型中评估了蛋氨酸限制饮食（MRD）喂养的抗肿瘤免疫作用。本研究在体外和体内研究了蛋氨酸和含YTH结构域家族蛋白1（YTHDF 1）在肿瘤免疫逃逸中的作用机制。还研究了MRD或YTHDF 1消耗与PD-1阻断的协同作用。我们发现，在不同的小鼠模型中，饮食蛋氨酸限制通过增加肿瘤浸润性CD 8 + T细胞的数量和细胞毒性来减少肿瘤生长并增强抗肿瘤免疫力。从机制上讲，来源于甲硫氨酸代谢的S-腺苷甲硫氨酸促进肿瘤细胞中免疫检查点（包括PD-L1和T细胞活化V结构域IG抑制因子（VISTA））的N6-甲基腺苷（m6 A）甲基化和翻译。此外，MRD或m6 A特异性结合蛋白YTHDF 1消耗通过恢复CD 8 + T细胞的浸润来抑制肿瘤生长，并与PD-1阻断协同作用以更好地控制肿瘤。在临床上，YTHDF 1表达与癌症患者的不良预后和免疫治疗结果相关。Methylamine和YTHDF 1通过调节T细胞的功能在抗癌免疫中发挥关键作用。靶向蛋氨酸代谢或YTHDF 1可能是癌症免疫治疗的潜在新策略。
Methionine metabolism is involved in a myriad of cellular functions, including methylation reactions and redox maintenance. Nevertheless, it remains unclear whether methionine metabolism, RNA methylation and antitumour immunity are molecularly intertwined. The antitumour immunity effect of methionine-restricted diet (MRD) feeding was assessed in murine models. The mechanisms of methionine and YTH domain-containing family protein 1 (YTHDF1) in tumour immune escape were determined in vitro and in vivo. The synergistic effects of MRD or YTHDF1 depletion with PD-1 blockade were also investigated. We found that dietary methionine restriction reduced tumour growth and enhanced antitumour immunity by increasing the number and cytotoxicity of tumour-infiltrating CD8+ T cells in different mouse models. Mechanistically, the S-adenosylmethionine derived from methionine metabolism promoted the N6-methyladenosine (m6A) methylation and translation of immune checkpoints, including PD-L1 and V-domain Ig suppressor of T cell activation (VISTA), in tumour cells. Furthermore, MRD or m6A-specific binding protein YTHDF1 depletion inhibited tumour growth by restoring the infiltration of CD8+ T cells, and synergised with PD-1 blockade for better tumour control. Clinically, YTHDF1 expression correlated with poor prognosis and immunotherapy outcomes for cancer patients. Methionine and YTHDF1 play a critical role in anticancer immunity through regulating the functions of T cells. Targeting methionine metabolism or YTHDF1 could be a potential new strategy for cancer immunotherapy.
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DOI：
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发表时间：
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影响因子：
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作者：
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DOI：
10.1084/jem.20210279
发表时间：
2021-08-02
期刊：
The Journal of experimental medicine
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