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Tumor methionine metabolism drives T-cell exhaustion in hepatocellular carcinoma

Author

Listed:
  • Man Hsin Hung

    (Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute)

  • Joo Sang Lee

    (Cancer Data Science Lab, National Cancer Institute, National Institutes of Health)

  • Chi Ma

    (Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health)

  • Laurence P. Diggs

    (Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health)

  • Sophia Heinrich

    (Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute)

  • Ching Wen Chang

    (Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute)

  • Lichun Ma

    (Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute)

  • Marshonna Forgues

    (Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute)

  • Anuradha Budhu

    (Liver Cancer Program, Center for Cancer Research, National Cancer Institute)

  • Jittiporn Chaisaingmongkol

    (Laboratory of Chemical Carcinogenesis, Chulabhorn Research Institute)

  • Mathuros Ruchirawat

    (Laboratory of Chemical Carcinogenesis, Chulabhorn Research Institute
    Center of Excellence on Environmental Health and Toxicology, Office of Higher Education Commission, Ministry of Education)

  • Eytan Ruppin

    (Cancer Data Science Lab, National Cancer Institute, National Institutes of Health)

  • Tim F. Greten

    (Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health
    Liver Cancer Program, Center for Cancer Research, National Cancer Institute)

  • Xin Wei Wang

    (Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute
    Liver Cancer Program, Center for Cancer Research, National Cancer Institute)

Abstract

T-cell exhaustion denotes a hypofunctional state of T lymphocytes commonly found in cancer, but how tumor cells drive T-cell exhaustion remains elusive. Here, we find T-cell exhaustion linked to overall survival in 675 hepatocellular carcinoma (HCC) patients with diverse ethnicities and etiologies. Integrative omics analyses uncover oncogenic reprograming of HCC methionine recycling with elevated 5-methylthioadenosine (MTA) and S-adenosylmethionine (SAM) to be tightly linked to T-cell exhaustion. SAM and MTA induce T-cell dysfunction in vitro. Moreover, CRISPR-Cas9-mediated deletion of MAT2A, a key SAM producing enzyme, results in an inhibition of T-cell dysfunction and HCC growth in mice. Thus, reprogramming of tumor methionine metabolism may be a viable therapeutic strategy to improve HCC immunity.

Suggested Citation

  • Man Hsin Hung & Joo Sang Lee & Chi Ma & Laurence P. Diggs & Sophia Heinrich & Ching Wen Chang & Lichun Ma & Marshonna Forgues & Anuradha Budhu & Jittiporn Chaisaingmongkol & Mathuros Ruchirawat & Eyta, 2021. "Tumor methionine metabolism drives T-cell exhaustion in hepatocellular carcinoma," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21804-1
    DOI: 10.1038/s41467-021-21804-1
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    Cited by:

    1. 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.
    2. Lichun Ma & Sophia Heinrich & Limin Wang & Friederike L. Keggenhoff & Subreen Khatib & Marshonna Forgues & Michael Kelly & Stephen M. Hewitt & Areeba Saif & Jonathan M. Hernandez & Donna Mabry & Roman, 2022. "Multiregional single-cell dissection of tumor and immune cells reveals stable lock-and-key features in liver cancer," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. 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.
    4. Mrinal Gounder & Melissa Johnson & Rebecca S. Heist & Geoffrey I. Shapiro & Sophie Postel-Vinay & Frederick H. Wilson & Elena Garralda & Gerburg Wulf & Caroline Almon & Salah Nabhan & Elia Aguado-Frai, 2025. "MAT2A inhibitor AG-270/S095033 in patients with advanced malignancies: a phase I trial," Nature Communications, Nature, vol. 16(1), pages 1-11, December.

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