The folate cycle enzyme MTHFD2 induces cancer immune evasion through PD-L1 up-regulation.
The folate cycle enzyme MTHFD2 induces cancer immune evasion through PD-L1 up-regulation.
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叶酸循环酶 MTHFD2 通过上调 PD-L1 诱导癌症免疫逃避
DOI：
10.1038/s41467-021-22173-5
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发表时间：
2021-03-29
影响因子：
16.6
通讯作者：
Wang T
中科院分区：
文献类型：
--
作者：
Shang M;Yang H;Yang R;Chen T;Fu Y;Li Y;Fang X;Zhang K;Zhang J;Li H;Cao X;Gu J;Xiao J;Zhang Q;Liu X;Yu Q;Wang T
代谢酶和代谢物在调节免疫攻击能力的免疫细胞信号传导中显示非代谢功能。然而，肿瘤的代谢重塑是否以及如何有助于其免疫抵抗仍有待澄清。在这里，我们进行了功能筛选的代谢基因，拯救肿瘤细胞的效应T细胞的细胞毒性，并确定胚胎和肿瘤特异性叶酸循环酶亚甲基四氢叶酸脱氢酶2（MTHFD 2）。在机制上，MTHFD 2促进基础和IFN-γ刺激的PD-L1表达，这是体内肿瘤发生所必需的。此外，IFN-γ通过AKT-mTORC 1途径刺激MTHFD 2。同时，MTHFD 2驱动叶酸循环以维持足够的尿苷相关代谢物，包括UDP-GlcNAc，其促进包括cMYC在内的蛋白质的整体O-GlcNAc化，从而增加cMYC稳定性和PD-L1转录。因此，胰腺癌患者中O-GlcNAc化水平与MTHFD 2和PD-L1呈正相关。这些发现揭示了MTHFD 2在细胞信号传导和癌症生物学中的非代谢作用。据报道，代谢物不仅支持癌细胞的高要求能量需求，而且还作为信号调节剂。在这里，作者表明，叶酸循环酶MTHFD 2的活性刺激PD-L1表达，削弱T细胞介导的细胞毒性并促进肿瘤发生。
Metabolic enzymes and metabolites display non-metabolic functions in immune cell signalling that modulate immune attack ability. However, whether and how a tumour’s metabolic remodelling contributes to its immune resistance remain to be clarified. Here we perform a functional screen of metabolic genes that rescue tumour cells from effector T cell cytotoxicity, and identify the embryo- and tumour-specific folate cycle enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2). Mechanistically, MTHFD2 promotes basal and IFN-γ-stimulated PD-L1 expression, which is necessary for tumourigenesis in vivo. Moreover, IFN-γ stimulates MTHFD2 through the AKT–mTORC1 pathway. Meanwhile, MTHFD2 drives the folate cycle to sustain sufficient uridine-related metabolites including UDP-GlcNAc, which promotes the global O-GlcNAcylation of proteins including cMYC, resulting in increased cMYC stability and PD-L1 transcription. Consistently, the O-GlcNAcylation level positively correlates with MTHFD2 and PD-L1 in pancreatic cancer patients. These findings uncover a non-metabolic role for MTHFD2 in cell signalling and cancer biology. Metabolites have been reported not only to support the highly-demanding energetic needs of cancer cells but also as signalling regulators. Here, the authors show that the activity of the folate cycle enzyme MTHFD2 stimulates PD-L1 expression impairing T cell-mediated cytotoxicity and promoting tumourigenesis.
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DOI：
10.1126/science.aac9935
发表时间：
2016-04-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Casey SC;Tong L;Li Y;Do R;Walz S;Fitzgerald KN;Gouw AM;Baylot V;Gütgemann I;Eilers M;Felsher DW
通讯作者：
Felsher DW
影响因子：
3.9
作者：
Mezquita, Laura;Planchard, David
通讯作者：
Planchard, David
影响因子：
4.7
作者：
Baldini SF;Lefebvre T
通讯作者：
Lefebvre T
影响因子：
4.7
作者：
Le Bourgeois T;Strauss L;Aksoylar HI;Daneshmandi S;Seth P;Patsoukis N;Boussiotis VA
通讯作者：
Boussiotis VA
影响因子：
64.5
作者：
Buck MD;Sowell RT;Kaech SM;Pearce EL
通讯作者：
Pearce EL