The folate cycle enzyme MTHFD2 induces cancer immune evasion through PD-L1 up-regulation
Shang Man, Yang Huijie, Yang Ran, Chen Tao, Fu Yuan, Li Yeyi, Fang Xianlong, Zhang Kangjian, Zhang Jianju, Li Hui, Cao Xueping, Gu Jinfa, Xiao Jianwen, Zhang Qi, Liu Xinyuan, Yu Qiujing, Wang Ting
Journal：Nature Communications
IF：14.92
DOI：10.1038/s41467-021-22173-5
PMID：33782411
Published：2021-03-29
research field：肿瘤学微生物组研究免疫学宏基因组学系统生物学癌症免疫治疗
Abstract
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.
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