Cancer SLC43A2 alters T cell methionine metabolism and histone methylation

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 and Weiping Zou ()
Additional contact information
Yingjie Bian: University of Michigan School of Medicine
Wei Li: University of Michigan School of Medicine
Daniel M. Kremer: University of Michigan Medical School
Peter Sajjakulnukit: University of Michigan Medical School
Shasha Li: University of Michigan School of Medicine
Joel Crespo: University of Michigan School of Medicine
Zeribe C. Nwosu: University of Michigan Medical School
Li Zhang: University of Michigan Medical School
Arkadiusz Czerwonka: Maria Curie-Skłodowska University
Anna Pawłowska: Medical University of Lublin
Houjun Xia: University of Michigan School of Medicine
Jing Li: University of Michigan School of Medicine
Peng Liao: University of Michigan School of Medicine
Jiali Yu: University of Michigan School of Medicine
Linda Vatan: University of Michigan School of Medicine
Wojciech Szeliga: University of Michigan School of Medicine
Shuang Wei: University of Michigan School of Medicine
Sara Grove: University of Michigan School of Medicine
J. Rebecca Liu: University of Michigan
Karen McLean: University of Michigan
Marcin Cieslik: University of Michigan
Arul M. Chinnaiyan: University of Michigan
Witold Zgodziński: Medical University of Lublin
Grzegorz Wallner: Medical University of Lublin
Iwona Wertel: Medical University of Lublin
Karolina Okła: Medical University of Lublin
Ilona Kryczek: University of Michigan School of Medicine
Costas A. Lyssiotis: University of Michigan Medical School
Weiping Zou: University of Michigan School of Medicine

Nature, 2020, vol. 585, issue 7824, 277-282

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2682-1

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