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

Man Shang,Jianju Zhang,Hui Li,Xueping Cao,Tao Chen,Qi Zhang,Yuan Fu,Ting Wang,Qiujing Yu,Xianlong Fang,Ran Yang,Jinfa Gu,Huijie Yang,Jianwen Xiao,Kangjian Zhang,Yeyi Li,Xinyuan Liu

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.

Highlights

Metabolic enzymes and metabolites display non-metabolic functions in immune cell signalling that modulate immune attack ability
To investigate whether and how metabolic remodeling in tumor cells contributes to their resistance against T cell cytotoxicity, we sought to identify metabolic genes meeting two criteria: first, that they are upregulated during tumourigenesis; second, that they rescue tumor cells from effector T cells
The Z-scores of 3261 genes were evaluated by MAGeCK, and the sgRNAs of 72 genes were highly (Z-score < −3) decreased after T cell treatment (Fig. 1a, right and Supplementary Data 1), suggesting that they are probably required for resisting T cell cytotoxicity

Summary

Introduction

Metabolic enzymes and metabolites display non-metabolic functions in immune cell signalling that modulate immune attack ability. PD-L1 mRNA (Fig. 2c) and protein (Fig. 2d, e) were decreased in MTHFD2 KD and KO human cancer cells, as well as in mouse embryonic fibroblasts (MEFs) (Fig. 2f). To determine whether MTHFD2 is involved in IFN-γ-stimulated PD-L1 expression, we examined its mRNA and protein levels in 786-O, A549, MCF7, HepG2, and HCT-116 cells.

Results

Conclusion