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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aminohydrolases / antagonists & inhibitors
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Aminohydrolases / genetics*
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Aminohydrolases / immunology
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Animals
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B7-H1 Antigen / antagonists & inhibitors
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B7-H1 Antigen / genetics*
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B7-H1 Antigen / immunology
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Carcinogenesis / genetics*
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Carcinogenesis / immunology
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Carcinogenesis / pathology
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Cell Line, Tumor
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Embryo, Mammalian
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Fibroblasts / immunology
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Fibroblasts / pathology
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Folic Acid / immunology
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Folic Acid / metabolism
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Gene Expression Regulation, Neoplastic*
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Humans
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Male
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Mechanistic Target of Rapamycin Complex 1 / genetics
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Mechanistic Target of Rapamycin Complex 1 / immunology
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Methylenetetrahydrofolate Dehydrogenase (NADP) / antagonists & inhibitors
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Methylenetetrahydrofolate Dehydrogenase (NADP) / genetics*
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Methylenetetrahydrofolate Dehydrogenase (NADP) / immunology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Nude
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Multifunctional Enzymes / antagonists & inhibitors
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Multifunctional Enzymes / genetics*
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Multifunctional Enzymes / immunology
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Pancreatic Neoplasms / genetics*
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Pancreatic Neoplasms / immunology
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Pancreatic Neoplasms / pathology
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Primary Cell Culture
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Protein Processing, Post-Translational*
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / immunology
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Proto-Oncogene Proteins c-myc / antagonists & inhibitors
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / immunology
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RNA, Small Interfering / genetics
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RNA, Small Interfering / immunology
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Signal Transduction
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T-Lymphocytes, Cytotoxic / immunology*
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T-Lymphocytes, Cytotoxic / pathology
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Tumor Burden
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Tumor Escape
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Uridine Diphosphate N-Acetylglucosamine / metabolism
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Xenograft Model Antitumor Assays
Substances
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B7-H1 Antigen
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CD274 protein, human
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MTHFD2 protein, human
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MYC protein, human
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Multifunctional Enzymes
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Proto-Oncogene Proteins c-myc
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RNA, Small Interfering
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Uridine Diphosphate N-Acetylglucosamine
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Folic Acid
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Methylenetetrahydrofolate Dehydrogenase (NADP)
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Mechanistic Target of Rapamycin Complex 1
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Proto-Oncogene Proteins c-akt
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Aminohydrolases