Journal
NATURE
Volume 585, Issue 7824, Pages 277-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-020-2682-1
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Funding
- Advanced Genomics Core and Bioinformatics Core of the University of Michigan Medical School's Biomedical Research Core Facilities
- US NIH/NCI [CA217648, CA123088, CA099985, CA193136, CA152470]
- NCI Cooperative Human Tissue Network (CHTN)
- 2017 AACR NextGen Grant for Transformative Cancer Research [17-20-01-LYSS]
- ACS Research Scholar Grant [RSG-18-186-01]
- NIH grant [DK097153]
- Charles Woodson Research Fund
- University of Michigan Pediatric Brain Tumor Initiative
- NIH through the University of Michigan Rogel Cancer Center Grant [P30 CA046592]
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Expression of the transporter SLC43A2 by tumour cells allows them to outcompete T cells for methionine and thereby disrupt the survival and function of tumour-infiltrating T cells. Abnormal epigenetic patterns correlate with effector T cell malfunction in tumours(1-4), but the cause of this link is unknown. Here we show that tumour cells disrupt methionine metabolism in CD8(+)T cells, thereby lowering intracellular levels of methionine and the methyl donorS-adenosylmethionine (SAM) and resulting in loss of dimethylation at lysine 79 of histone H3 (H3K79me2). Loss of H3K79me2 led to low expression of STAT5 and impaired T cell immunity. Mechanistically, tumour cells avidly consumed methionine and outcompeted T cells for methionine by expressing high levels of the methionine transporter SLC43A2. Genetic and biochemical inhibition of tumour SLC43A2 restored H3K79me2 in T cells, thereby boosting spontaneous and checkpoint-induced tumour immunity. Moreover, methionine supplementation improved the expression of H3K79me2 and STAT5 in T cells, and this was accompanied by increased T cell immunity in tumour-bearing mice and patients with colon cancer. Clinically, tumour SLC43A2 correlated negatively with T cell histone methylation and functional gene signatures. Our results identify a mechanistic connection between methionine metabolism, histone patterns, and T cell immunity in the tumour microenvironment. Thus, cancer methionine consumption is an immune evasion mechanism, and targeting cancer methionine signalling may provide an immunotherapeutic approach.
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