1. Academic Validation
  2. ARID1A loss induces polymorphonuclear myeloid-derived suppressor cell chemotaxis and promotes prostate cancer progression

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

  • Nat Commun. 2022 Nov 26;13(1):7281. doi: 10.1038/s41467-022-34871-9.
Ni Li # 1 Qiuli Liu # 2 Ying Han # 3 Siyu Pei # 3 Bisheng Cheng 4 Junyu Xu 5 Xiang Miao 3 Qiang Pan 3 Hanling Wang 3 Jiacheng Guo 3 Xuege Wang 3 Guoying Zhang 3 Yannan Lian 3 Wei Zhang 3 Yi Zang 3 Minjia Tan 5 Qintong Li 6 Xiaoming Wang 7 Yichuan Xiao 3 Guohong Hu 3 Jun Jiang 8 Hai Huang 9 Jun Qin 10 11
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China. lini@sibs.ac.cn.
  • 2 Department of Urology, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing, 400042, China.
  • 3 CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China.
  • 4 Department of Urology, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong Provincial Clinical Research Center for Urological Diseases, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
  • 5 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 6 Department of Obstetrics, Gynecology and Pediatrics, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, 20 Renmin South Road, Chengdu, 610041, China.
  • 7 Department of Immunology, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, 101 Longmian Ave, Nanjing, 211166, China.
  • 8 Department of Urology, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing, 400042, China. jiangjun_64@163.com.
  • 9 Department of Urology, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong Provincial Clinical Research Center for Urological Diseases, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China. huangh9@mail.sysu.edu.cn.
  • 10 CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China. qinjun@sibs.ac.cn.
  • 11 Department of Urology, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing, 400042, China. qinjun@sibs.ac.cn.
  • # Contributed equally.
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.

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