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Cancer SLC43A2 alters T cell methionine metabolism and histone methylation

Author

Listed:
  • Yingjie Bian

    (University of Michigan School of Medicine
    University of Michigan Rogel Cancer Center, University of Michigan School of Medicine)

  • Wei Li

    (University of Michigan School of Medicine
    University of Michigan Rogel Cancer Center, 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
    University of Michigan Rogel Cancer Center, University of Michigan School of Medicine
    University of Michigan)

  • Joel Crespo

    (University of Michigan School of Medicine
    University of Michigan Rogel Cancer Center, 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
    University of Michigan Rogel Cancer Center, University of Michigan School of Medicine)

  • Jing Li

    (University of Michigan School of Medicine
    University of Michigan Rogel Cancer Center, University of Michigan School of Medicine)

  • Peng Liao

    (University of Michigan School of Medicine
    University of Michigan Rogel Cancer Center, University of Michigan School of Medicine)

  • Jiali Yu

    (University of Michigan School of Medicine
    University of Michigan Rogel Cancer Center, University of Michigan School of Medicine)

  • Linda Vatan

    (University of Michigan School of Medicine
    University of Michigan Rogel Cancer Center, University of Michigan School of Medicine)

  • Wojciech Szeliga

    (University of Michigan School of Medicine
    University of Michigan Rogel Cancer Center, University of Michigan School of Medicine)

  • Shuang Wei

    (University of Michigan School of Medicine
    University of Michigan Rogel Cancer Center, University of Michigan School of Medicine)

  • Sara Grove

    (University of Michigan School of Medicine
    University of Michigan Rogel Cancer Center, University of Michigan School of Medicine)

  • J. Rebecca Liu

    (University of Michigan)

  • Karen McLean

    (University of Michigan)

  • Marcin Cieslik

    (University of Michigan
    University of Michigan)

  • Arul M. Chinnaiyan

    (University of Michigan
    University of Michigan
    University of Michigan
    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
    University of Michigan Rogel Cancer Center, University of Michigan School of Medicine)

  • Costas A. Lyssiotis

    (University of Michigan Medical School
    University of Michigan Medical School
    University of Michigan School of Medicine
    University of Michigan School of Medicine)

  • Weiping Zou

    (University of Michigan School of Medicine
    University of Michigan Rogel Cancer Center, University of Michigan School of Medicine
    University of Michigan
    University of Michigan School of Medicine)

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.

Suggested Citation

  • 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 , 2020. "Cancer SLC43A2 alters T cell methionine metabolism and histone methylation," Nature, Nature, vol. 585(7824), pages 277-282, September.
  • Handle: RePEc:nat:nature:v:585:y:2020:i:7824:d:10.1038_s41586-020-2682-1
    DOI: 10.1038/s41586-020-2682-1
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    Cited by:

    1. Le Tran Phuc Khoa & Wentao Yang & Mengrou Shan & Li Zhang & Fengbiao Mao & Bo Zhou & Qiang Li & Rebecca Malcore & Clair Harris & Lili Zhao & Rajesh C. Rao & Shigeki Iwase & Sundeep Kalantry & Stephani, 2024. "Quiescence enables unrestricted cell fate in naive embryonic stem cells," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Ying Huang & Geng Qin & TingTing Cui & Chuanqi Zhao & Jinsong Ren & Xiaogang Qu, 2023. "A bimetallic nanoplatform for STING activation and CRISPR/Cas mediated depletion of the methionine transporter in cancer cells restores anti-tumor immune responses," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Zenan Wang & Binghao Li & Shan Li & Wenlong Lin & Zhan Wang & Shengdong Wang & Weida Chen & Wei Shi & Tao Chen & Hao Zhou & Eloy Yinwang & Wenkan Zhang & Haochen Mou & Xupeng Chai & Jiahao Zhang & Zhi, 2022. "Metabolic control of CD47 expression through LAT2-mediated amino acid uptake promotes tumor immune evasion," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    4. Mahesh Pandit & Yun-Seo Kil & Jae-Hee Ahn & Ram Hari Pokhrel & Ye Gu & Sunil Mishra & Youngjoo Han & Yung-Taek Ouh & Ben Kang & Myeong Seon Jeong & Jong-Oh Kim & Joo-Won Nam & Hyun-Jeong Ko & Jae-Hoon, 2023. "Methionine consumption by cancer cells drives a progressive upregulation of PD-1 expression in CD4 T cells," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    5. Wenfeng Ren & Zilong Xu & Yating Chang & Fei Ju & Hongning Wu & Zhiqi Liang & Min Zhao & Naizhen Wang & Yanhua Lin & Chenhang Xu & Shengming Chen & Yipeng Rao & Chaolong Lin & Jianxin Yang & Pingguo L, 2024. "Pharmaceutical targeting of OTUB2 sensitizes tumors to cytotoxic T cells via degradation of PD-L1," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    6. Hanhan Ning & Shan Huang & Yang Lei & Renyong Zhi & Han Yan & Jiaxing Jin & Zhenyu Hu & Kaimin Guo & Jinhua Liu & Jie Yang & Zhe Liu & Yi Ba & Xin Gao & Deqing Hu, 2022. "Enhancer decommissioning by MLL4 ablation elicits dsRNA-interferon signaling and GSDMD-mediated pyroptosis to potentiate anti-tumor immunity," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    7. Chunge Zhong & Wen-Jie Jiang & Yingjia Yao & Zexu Li & You Li & Shengnan Wang & Xiaofeng Wang & Wenjuan Zhu & Siqi Wu & Jing Wang & Shuangshuang Fan & Shixin Ma & Yeshu Liu & Han Zhang & Wenchang Zhao, 2024. "CRISPR screens reveal convergent targeting strategies against evolutionarily distinct chemoresistance in cancer," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    8. Ying Xue & Fujia Lu & Zhenzhen Chang & Jing Li & Yuan Gao & Jie Zhou & Ying Luo & Yongfeng Lai & Siyuan Cao & Xiaoxiao Li & Yuhan Zhou & Yan Li & Zheng Tan & Xiang Cheng & Xiong Li & Jing Chen & Weimi, 2023. "Intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    9. Wen Fang & Liu Jiang & Yibing Zhu & Sen Yang & Hong Qiu & Jiou Cheng & Qingxi Liang & Zong-cai Tu & Cunqi Ye, 2023. "Methionine restriction constrains lipoylation and activates mitochondria for nitrogenic synthesis of amino acids," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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