2. Academic Validation
  3. 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

  • Nat Commun. 2021 Mar 29;12(1):1940. doi: 10.1038/s41467-021-22173-5.
Man Shang  # 1,  Huijie Yang  # 1,  Ran Yang 1,  Tao Chen 2,  Yuan Fu 1,  Yeyi Li 1,  Xianlong Fang 3,  Kangjian Zhang 3 4,  Jianju Zhang 5,  Hui Li 3,  Xueping Cao 3,  Jinfa Gu 3 4,  Jianwen Xiao 3,  Qi Zhang 6,  Xinyuan Liu 4,  Qiujing Yu 7,  Ting Wang 8
Affiliations

Affiliations

  • 1 Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, The province and ministry co-sponsored collaborative innovation center for medical epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
  • 2 Endoscopy Center, Shanghai East Hospital, Tongji University, Shanghai, China.
  • 3 Shanghai Yuansong Bio-technology Limited Company, Shanghai, China.
  • 4 State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Beijing, China.
  • 5 Department of Pediatric Surgery, Tianjin Medical University General Hospital, Tianjin, China.
  • 6 Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Integrative Medicine for Acute Abdominal Diseases, Integrated Chinese and Western Medicine Hospital (Nankai Hospital), Tianjin University, Tianjin, China.
  • 7 Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China. [email protected].
  • 8 Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, The province and ministry co-sponsored collaborative innovation center for medical epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China. [email protected].
  • # Contributed equally.
PMID: 33782411 DOI: 10.1038/s41467-021-22173-5
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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