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ARID1A loss induces polymorphonuclear myeloid-derived suppressor cell chemotaxis and promotes prostate cancer progression

Author

Listed:
  • Ni Li

    (University of Chinese Academy of Sciences)

  • Qiuli Liu

    (Army Medical University)

  • Ying Han

    (University of Chinese Academy of Sciences)

  • Siyu Pei

    (University of Chinese Academy of Sciences)

  • Bisheng Cheng

    (Sun Yat-sen Memorial Hospital, Sun Yat-sen University)

  • Junyu Xu

    (Chinese Academy of Sciences)

  • Xiang Miao

    (University of Chinese Academy of Sciences)

  • Qiang Pan

    (University of Chinese Academy of Sciences)

  • Hanling Wang

    (University of Chinese Academy of Sciences)

  • Jiacheng Guo

    (University of Chinese Academy of Sciences)

  • Xuege Wang

    (University of Chinese Academy of Sciences)

  • Guoying Zhang

    (University of Chinese Academy of Sciences)

  • Yannan Lian

    (University of Chinese Academy of Sciences)

  • Wei Zhang

    (University of Chinese Academy of Sciences)

  • Yi Zang

    (University of Chinese Academy of Sciences)

  • Minjia Tan

    (Chinese Academy of Sciences)

  • Qintong Li

    (Sichuan University)

  • Xiaoming Wang

    (Nanjing Medical University)

  • Yichuan Xiao

    (University of Chinese Academy of Sciences)

  • Guohong Hu

    (University of Chinese Academy of Sciences)

  • Jun Jiang

    (Army Medical University)

  • Hai Huang

    (Sun Yat-sen Memorial Hospital, Sun Yat-sen University)

  • Jun Qin

    (University of Chinese Academy of Sciences
    Army Medical University)

Abstract

Chronic inflammation and an immunosuppressive microenvironment promote prostate cancer (PCa) progression and diminish the response to immune checkpoint blockade (ICB) therapies. However, it remains unclear how and to what extent these two events are coordinated. Here, we show that ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, functions downstream of inflammation-induced IKKβ activation to shape the immunosuppressive tumor microenvironment (TME). Prostate-specific deletion of Arid1a cooperates with Pten loss to accelerate prostate tumorigenesis. We identify polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) as the major infiltrating immune cell type that causes immune evasion and reveal that neutralization of PMN-MDSCs restricts the progression of Arid1a-deficient tumors. Mechanistically, inflammatory cues activate IKKβ to phosphorylate ARID1A, leading to its degradation via β-TRCP. ARID1A downregulation in turn silences the enhancer of A20 deubiquitinase, a critical negative regulator of NF-κB signaling, and thereby unleashes CXCR2 ligand-mediated MDSC chemotaxis. Importantly, our results support the therapeutic strategy of anti-NF-κB antibody or targeting CXCR2 combined with ICB for advanced PCa. Together, our findings highlight that the IKKβ/ARID1A/NF-κB feedback axis integrates inflammation and immunosuppression to promote PCa progression.

Suggested Citation

  • Ni Li & Qiuli Liu & Ying Han & Siyu Pei & Bisheng Cheng & Junyu Xu & Xiang Miao & Qiang Pan & Hanling Wang & Jiacheng Guo & Xuege Wang & Guoying Zhang & Yannan Lian & Wei Zhang & Yi Zang & Minjia Tan , 2022. "ARID1A loss induces polymorphonuclear myeloid-derived suppressor cell chemotaxis and promotes prostate cancer progression," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34871-9
    DOI: 10.1038/s41467-022-34871-9
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