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Oncofetal gene SALL4 reactivation by hepatitis B virus counteracts miR-200c in PD-L1-induced T cell exhaustion

Author

Listed:
  • Cheng Sun

    (University of Science and Technology of China
    College of Medicine, Zhejiang University)

  • Peixiang Lan

    (Shandong University)

  • Qiuju Han

    (Shandong University)

  • Mei Huang

    (Anhui Provincial Hospital Affiliated with Anhui Medical University)

  • Zhihong Zhang

    (Huazhong University of Science and Technology)

  • Geliang Xu

    (Anhui Provincial Hospital Affiliated with Anhui Medical University)

  • Jiaxi Song

    (University of Science and Technology of China)

  • Jinyu Wang

    (University of Science and Technology of China)

  • Haiming Wei

    (University of Science and Technology of China)

  • Jian Zhang

    (Shandong University)

  • Rui Sun

    (University of Science and Technology of China)

  • Cai Zhang

    (Shandong University)

  • Zhigang Tian

    (University of Science and Technology of China
    College of Medicine, Zhejiang University)

Abstract

A chronic viral or tumor microenvironment can push T cells to exhaustion by promoting coinhibitory ligand expression. However, how host factors control coinhibitory ligand expression and whether viral infection breaks this control during tumor progress is unknown. Here we show a close negative correlation between SALL4 or PD-L1 and miR-200c in tumors from 98 patients with HBV-related hepatocellular carcinoma. SALL4 or PD-L1 expression correlates negatively with miR-200c expression, and patients with lower levels of SALL4 or PD-L1 and higher miR-200c survive longer. Moreover, over-expression of miR-200c antagonizes HBV-mediated PD-L1 expression by targeting 3ʹ-UTR of CD274 (encoding PD-L1) directly, and reverses antiviral CD8+ T cell exhaustion. MiR-200c transcription is inhibited by oncofetal protein SALL4, which is re-expressed through HBV-induced STAT3 activation in adulthood. We propose that an HBV-pSTAT3-SALL4-miR-200c axis regulates PD-L1. Therapeutic strategies to influence this axis might reverse virus-induced immune exhaustion.

Suggested Citation

  • Cheng Sun & Peixiang Lan & Qiuju Han & Mei Huang & Zhihong Zhang & Geliang Xu & Jiaxi Song & Jinyu Wang & Haiming Wei & Jian Zhang & Rui Sun & Cai Zhang & Zhigang Tian, 2018. "Oncofetal gene SALL4 reactivation by hepatitis B virus counteracts miR-200c in PD-L1-induced T cell exhaustion," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03584-3
    DOI: 10.1038/s41467-018-03584-3
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