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

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, Qintong Li, Xiaoming Wang, Yichuan Xiao, Guohong Hu, Jun Jiang (), Hai Huang () and Jun Qin ()
Additional contact information
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

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34871-9

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