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Inhibition of UBA6 by inosine augments tumour immunogenicity and responses

Author

Listed:
  • Lei Zhang

    (Shanghai JiaoTong University School of Medicine
    Shanghai Jiao Tong University School of Medicine)

  • Li Jiang

    (Shanghai Jiao Tong University School of Medicine)

  • Liang Yu

    (Shanghai Jiao Tong University School of Medicine)

  • Qin Li

    (Capital Medical University)

  • Xiangjun Tian

    (The University of Texas MD Anderson Cancer Center)

  • Jingquan He

    (Biotree Institute of Health)

  • Ling Zeng

    (Shanghai JiaoTong University School of Medicine
    Shanghai Jiao Tong University School of Medicine)

  • Yuqin Yang

    (Shanghai Jiao Tong University School of Medicine)

  • Chaoran Wang

    (Capital Medical University)

  • Yuhan Wei

    (Capital Medical University)

  • Xiaoyue Jiang

    (Capital Medical University)

  • Jing Li

    (The Affiliated Hospital of Qingdao University)

  • Xiaolu Ge

    (Shanghai JiaoTong University School of Medicine
    Shanghai Jiao Tong University School of Medicine)

  • Qisheng Gu

    (Shanghai Jiao Tong University School of Medicine)

  • Jikun Li

    (Shanghai Jiao Tong University School of Medicine)

  • Di Wu

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill)

  • Anthony J. Sadler

    (Hudson Institute of Medical Research
    Monash University)

  • Di Yu

    (The University of Queensland)

  • Dakang Xu

    (Shanghai Jiao Tong University School of Medicine)

  • Yue Gao

    (Beijing Institute of Radiation Medicine)

  • Xiangliang Yuan

    (Shanghai Jiao Tong University School of Medicine)

  • Baokun He

    (Shanghai JiaoTong University School of Medicine
    Shanghai Jiao Tong University School of Medicine
    Guangzhou University of Chinese Medicine)

Abstract

Anti-cancer immunity and response to immune therapy is influenced by the metabolic states of the tumours. Immune checkpoint blockade therapy (ICB) is known to involve metabolic adaptation, however, the mechanism is not fully known. Here we show, by metabolic profiling of plasma samples from melanoma-bearing mice undergoing anti-PD1 and anti-CTLA4 combination therapy, that higher levels of purine metabolites, including inosine, mark ICB sensitivity. Metabolic profiles of ICB-treated human cancers confirm the association between inosine levels and ICB sensitivity. In mouse models, inosine supplementation sensitizes tumours to ICB, even if they are intrinsically ICB resistant, by enhancing T cell-mediated cytotoxicity and hence generating an immunologically hotter microenvironment. We find that inosine directly inhibits UBA6 in tumour cells, and lower level of UBA6 makes the tumour more immunogenic and this is reflected in favourable outcome following ICB therapy in human melanomas. Transplanted mouse melanoma and breast cancer cells with genetic ablation of Uba6 show higher sensitivity to ICB than wild type tumours. Thus, we provide evidence of an inosine-regulated UBA6-dependent pathway governing tumour-intrinsic immunogenicity and hence sensitivity to immune checkpoint inhibition, which might provide targets to overcome ICB resistance.

Suggested Citation

  • Lei Zhang & Li Jiang & Liang Yu & Qin Li & Xiangjun Tian & Jingquan He & Ling Zeng & Yuqin Yang & Chaoran Wang & Yuhan Wei & Xiaoyue Jiang & Jing Li & Xiaolu Ge & Qisheng Gu & Jikun Li & Di Wu & Antho, 2022. "Inhibition of UBA6 by inosine augments tumour immunogenicity and responses," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33116-z
    DOI: 10.1038/s41467-022-33116-z
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