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HKDC1 promotes tumor immune evasion in hepatocellular carcinoma by coupling cytoskeleton to STAT1 activation and PD-L1 expression

Author

Listed:
  • Yi Zhang

    (South China University of Technology)

  • Mingjie Wang

    (South China University of Technology
    Southern Medical University)

  • Ling Ye

    (University of Science and Technology of China)

  • Shengqi Shen

    (Southern Medical University)

  • Yuxi Zhang

    (South China University of Technology)

  • Xiaoyu Qian

    (South China University of Technology)

  • Tong Zhang

    (Southern Medical University)

  • Mengqiu Yuan

    (University of Science and Technology of China)

  • Zijian Ye

    (South China University of Technology)

  • Jin Cai

    (South China University of Technology)

  • Xiang Meng

    (South China University of Technology)

  • Shiqiao Qiu

    (South China University of Technology)

  • Shengzhi Liu

    (South China University of Technology)

  • Rui Liu

    (University of Science and Technology of China)

  • Weidong Jia

    (University of Science and Technology of China)

  • Xianzhu Yang

    (South China University of Technology, Guangzhou International Campus)

  • Huafeng Zhang

    (University of Science and Technology of China)

  • Xiuying Zhong

    (Southern Medical University)

  • Ping Gao

    (South China University of Technology
    Southern Medical University)

Abstract

Immune checkpoint blockade (ICB) has shown considerable promise for treating various malignancies, but only a subset of cancer patients benefit from immune checkpoint inhibitor therapy because of immune evasion and immune-related adverse events (irAEs). The mechanisms underlying how tumor cells regulate immune cell response remain largely unknown. Here we show that hexokinase domain component 1 (HKDC1) promotes tumor immune evasion in a CD8+ T cell-dependent manner by activating STAT1/PD-L1 in tumor cells. Mechanistically, HKDC1 binds to and presents cytosolic STAT1 to IFNGR1 on the plasma membrane following IFNγ-stimulation by associating with cytoskeleton protein ACTA2, resulting in STAT1 phosphorylation and nuclear translocation. HKDC1 inhibition in combination with anti-PD-1/PD-L1 enhances in vivo T cell antitumor response in liver cancer models in male mice. Clinical sample analysis indicates a correlation among HKDC1 expression, STAT1 phosphorylation, and survival in patients with hepatocellular carcinoma treated with atezolizumab (anti-PD-L1). These findings reveal a role for HKDC1 in regulating immune evasion by coupling cytoskeleton with STAT1 activation, providing a potential combination strategy to enhance antitumor immune responses.

Suggested Citation

  • Yi Zhang & Mingjie Wang & Ling Ye & Shengqi Shen & Yuxi Zhang & Xiaoyu Qian & Tong Zhang & Mengqiu Yuan & Zijian Ye & Jin Cai & Xiang Meng & Shiqiao Qiu & Shengzhi Liu & Rui Liu & Weidong Jia & Xianzh, 2024. "HKDC1 promotes tumor immune evasion in hepatocellular carcinoma by coupling cytoskeleton to STAT1 activation and PD-L1 expression," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45712-2
    DOI: 10.1038/s41467-024-45712-2
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