Original Article: https://doi.org/10.1038/s41586-020-2682-1
- Abnormal epigenetic patterns is associated with effector T cell malfunction in tumors, but the cause of this correlation is unclear.
- Methionine is an amino acid that is a component of most proteins, and it is an essential nutrient in the diet of vertebrates.
- CD8+ T cell is a T lymphocyte that kills cancer cells.
- The study show that tumor cells alter methionine metabolism in CD8+ T cells.
- The alteration includes lowering the intracellular levels of methionine inside the cells.
- The alteration also includes lowering the intracellular levels of methyl donor S-adenosylmethionine (SAM).
- The result of these alteration is the loss of dimethylation at lysine 79 of histone H3 (H3K79me2).
- Loss of H3K79me2 resulted in low expression of STAT5 and impaired T cell immunity.
- STAT5 proteins are involved in cytosolic signalling and in mediating the expression of specific genes.
- Mechanistically, tumor cells enthusiastically consumed methionine and outcompeted T cells.
- Tumor cells compete with T cell for methionine by expressing high levels of the methionine transporter.
- Genetic and biochemical inhibition of tumor methionine transporter restored H3K79me2 in T cells, as a result boosting spontaneous and checkpoint-induced tumor immunity.
- In addition, methionine supplement improved the expression of H3K79me2 and STAT5 in T cells.
- The improvement due to methionine supplementation went along with increased T cell immunity in tumor-bearing mice and patients with colon cancer.
- Clinically, tumor methionine transporter has a negative correlation with T cell histone methylation and functional gene signatures.
- The study identify a physical connection between methionine metabolism, histone patterns, and T cell immunity in the tumor micro-environment.
- Cancer methionine consumption can be an immune evasion mechanism.
- The study suggests that targeting cancer methionine signalling is a potential cancer therapy.