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Metabolic control of CD47 expression through LAT2-mediated amino acid uptake promotes tumor immune evasion

Author

Listed:
  • Zenan Wang

    (Zhejiang University School of Medicine
    Orthopedics Research Institute of Zhejiang University
    Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province)

  • Binghao Li

    (Zhejiang University School of Medicine
    Orthopedics Research Institute of Zhejiang University
    Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province)

  • Shan Li

    (Zhejiang University School of Medicine)

  • Wenlong Lin

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine)

  • Zhan Wang

    (Zhejiang University School of Medicine
    Orthopedics Research Institute of Zhejiang University
    Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province)

  • Shengdong Wang

    (Zhejiang University School of Medicine
    Orthopedics Research Institute of Zhejiang University
    Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province)

  • Weida Chen

    (Zhejiang University School of Medicine)

  • Wei Shi

    (Zhejiang University School of Medicine)

  • Tao Chen

    (Zhejiang University School of Medicine
    Orthopedics Research Institute of Zhejiang University
    Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province)

  • Hao Zhou

    (Zhejiang University School of Medicine
    Orthopedics Research Institute of Zhejiang University
    Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province)

  • Eloy Yinwang

    (Zhejiang University School of Medicine
    Orthopedics Research Institute of Zhejiang University
    Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province)

  • Wenkan Zhang

    (Zhejiang University School of Medicine
    Orthopedics Research Institute of Zhejiang University
    Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province)

  • Haochen Mou

    (Zhejiang University School of Medicine
    Orthopedics Research Institute of Zhejiang University
    Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province)

  • Xupeng Chai

    (Zhejiang University School of Medicine
    Orthopedics Research Institute of Zhejiang University
    Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province)

  • Jiahao Zhang

    (Zhejiang University School of Medicine
    Orthopedics Research Institute of Zhejiang University
    Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province)

  • Zhimin Lu

    (Zhejiang University School of Medicine
    Zhejiang University Cancer Center)

  • Zhaoming Ye

    (Zhejiang University School of Medicine
    Orthopedics Research Institute of Zhejiang University
    Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province)

Abstract

Chemotherapy elicits tumor immune evasion with poorly characterized mechanisms. Here, we demonstrate that chemotherapy markedly enhances the expression levels of CD47 in osteosarcoma tissues, which are positively associated with patient mortality. We reveal that macrophages in response to chemotherapy secrete interleukin-18, which in turn upregulates expression of L-amino acid transporter 2 (LAT2) in tumor cells for substantially enhanced uptakes of leucine and glutamine, two potent stimulators of mTORC1. The increased levels of leucine and enhanced glutaminolysis activate mTORC1 and subsequent c-Myc-mediated transcription of CD47. Depletion of LAT2 or treatment of tumor cells with a LAT inhibitor downregulates CD47 with enhanced macrophage infiltration and phagocytosis of tumor cells, and sensitizes osteosarcoma to doxorubicin treatment in mice. These findings unveil a mutual regulation between macrophage and tumor cells that plays a critical role in tumor immune evasion and underscore the potential to intervene with the LAT2-mediated amino acid uptake for improving cancer therapies.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34064-4
    DOI: 10.1038/s41467-022-34064-4
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    1. Marlies Cortés & Agnese Brischetto & M. C. Martinez-Campanario & Chiara Ninfali & Verónica Domínguez & Sara Fernández & Raquel Celis & Anna Esteve-Codina & Juan J. Lozano & Julia Sidorova & Gloria Gar, 2023. "Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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