The folate cycle enzyme MTHFD2 induces cancer immune evasion through PD-L1 up-regulation

Man Shang, Huijie Yang, Ran Yang, Tao Chen, Yuan Fu, Yeyi Li, Xianlong Fang, Kangjian Zhang, Jianju Zhang, Hui Li, Xueping Cao, Jinfa Gu, Jianwen Xiao, Qi Zhang, Xinyuan Liu, Qiujing Yu () and Ting Wang ()
Additional contact information
Man Shang: School of Basic Medical Sciences, Tianjin Medical University
Huijie Yang: School of Basic Medical Sciences, Tianjin Medical University
Ran Yang: School of Basic Medical Sciences, Tianjin Medical University
Tao Chen: Tongji University
Yuan Fu: School of Basic Medical Sciences, Tianjin Medical University
Yeyi Li: School of Basic Medical Sciences, Tianjin Medical University
Xianlong Fang: Shanghai Yuansong Bio-technology Limited Company
Kangjian Zhang: Shanghai Yuansong Bio-technology Limited Company
Jianju Zhang: Tianjin Medical University General Hospital
Hui Li: Shanghai Yuansong Bio-technology Limited Company
Xueping Cao: Shanghai Yuansong Bio-technology Limited Company
Jinfa Gu: Shanghai Yuansong Bio-technology Limited Company
Jianwen Xiao: Shanghai Yuansong Bio-technology Limited Company
Qi Zhang: Tianjin University
Xinyuan Liu: Chinese Academy of Sciences
Qiujing Yu: Tianjin Medical University
Ting Wang: School of Basic Medical Sciences, Tianjin Medical University

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-021-22173-5 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22173-5

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-22173-5

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().