Cancer SLC43A2 alters T cell methionine metabolism and histone methylation.

Abstract

Abnormal epigenetic patterns correlate with effector T cell malfunction in tumours1-4, 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 donor S-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.

• Authors: Yingjie Bian, Wei Li, Daniel M Kremer, Peter Sajjakulnukit, Shasha Li, Joel Crespo, Zeribe C Nwosu, Li Zhang, Arkadiusz Czerwonka, Anna Pawłowska, Houjun Xia, Jing Li, Peng Liao, Jiali Yu, Linda Vatan, Wojciech Szeliga, Shuang Wei, Sara Grove, J Rebecca Liu, Karen McLean, Marcin Cieslik, Arul M Chinnaiyan, Witold Zgodziński, Grzegorz Wallner, Iwona Wertel, Karolina Okła, Ilona Kryczek, Costas A Lyssiotis, Weiping Zou
• Journal: Nature (Nature) Vol. 585 Issue 7824 Pg. 277-282 (09 2020) ISSN: 1476-4687 [Electronic] England
• PMID: 32879489 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acid Transport System L
• Histones
• Receptors, Antigen, T-Cell
• STAT5 Transcription Factor
• Slc43a2 protein, mouse
• Methionine

Topics

• Amino Acid Transport System L (deficiency, metabolism)
• Animals
• CD8-Positive T-Lymphocytes (cytology, immunology, metabolism)
• Cell Line, Tumor
• Epigenesis, Genetic
• Female
• Histones (chemistry, metabolism)
• Humans
• Methionine (metabolism)
• Methylation
• Mice
• Neoplasms (genetics, immunology, metabolism, pathology)
• Receptors, Antigen, T-Cell (metabolism)
• STAT5 Transcription Factor (metabolism)