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

文献类型：期刊论文

作者Li, Ni2; Liu, Qiuli3; Han, Ying2; Pei, Siyu2; Cheng, Bisheng4; Xu, Junyu5; Miao, Xiang2; Pan, Qiang2; Wang, Hanling2; Guo, Jiacheng2
刊名NATURE COMMUNICATIONS
出版日期2022-11-26
卷号13期号:1页码:20
DOI10.1038/s41467-022-34871-9
通讯作者Li, Ni(lini@sibs.ac.cn) ; Jiang, Jun(jiangjun_64@163.com) ; Huang, Hai(huangh9@mail.sysu.edu.cn) ; Qin, Jun(qinjun@sibs.ac.cn)
英文摘要The accumulation of myeloid derived suppressor cells (MDSC) has been associated with prostate cancer progression and castration resistance. Here the authors show that loss of ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, results in polymorphonuclear-MDSC infiltration and cooperates with Pten loss to accelerate prostate tumorigenesis. 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 IKK beta 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 IKK beta to phosphorylate ARID1A, leading to its degradation via beta-TRCP. ARID1A downregulation in turn silences the enhancer of A20 deubiquitinase, a critical negative regulator of NF-kappa B signaling, and thereby unleashes CXCR2 ligand-mediated MDSC chemotaxis. Importantly, our results support the therapeutic strategy of anti-NF-kappa B antibody or targeting CXCR2 combined with ICB for advanced PCa. Together, our findings highlight that the IKK beta/ARID1A/NF-kappa B feedback axis integrates inflammation and immunosuppression to promote PCa progression.
WOS关键词NF-KAPPA-B ; SOMATIC MUTATIONS ; TUMOR PROGRESSION ; DOUBLE-BLIND ; IKK-BETA ; ENHANCER ; INFLAMMATION ; IPILIMUMAB ; SENESCENCE ; BORTEZOMIB
资助项目National Key Research and Development Program of China[2021YFA1300601] ; National Key Research and Development Program of China[2018YFA0902700] ; National Natural Science Foundation of China Projects[81825018] ; National Natural Science Foundation of China Projects[82130085] ; National Natural Science Foundation of China Projects[81773121] ; National Natural Science Foundation of China Projects[81802818] ; National Natural Science Foundation of China Projects[81974395] ; National Natural Science Foundation of China Projects[82173036] ; Shanghai Pilot Program for Basic Research-Chinese Academy of Science, Shanghai Branch[JCYJSHFY-2022-007] ; Chinese Academy of Sciences[QYZDBSSW-SMC052] ; Program of Shanghai Academic/Technology Research Leader[19XD1424300] ; Initiative Postdocs Supporting Program by MOHRSS ; National Postdoc Management Committee[bx201800247]
WOS研究方向Science & Technology - Other Topics
语种英语
出版者NATURE PORTFOLIO
WOS记录号WOS:000888871600019
源URL[http://119.78.100.183/handle/2S10ELR8/304401]  
专题新药研究国家重点实验室
通讯作者Li, Ni; Jiang, Jun; Huang, Hai; Qin, Jun
作者单位1.Sichuan Univ, Dept Obstet Gynecol & Pediat, West China Univ Hosp 2,Minist Educ, Key Lab Birth Defects & Related Dis Women & Child, 20 Renmin South Rd, Chengdu 610041, Peoples R China
2.Univ Chinese Acad Sci, Chinese Acad Sci, CAS Ctr Excellence Mol Cell Sci, Shanghai Inst Nutr & Hlth, 320 Yueyang Rd, Shanghai 200031, Peoples R China
3.Army Med Univ, Daping Hosp, Inst Surg Res, Dept Urol, Chongqing 400042, Peoples R China
4.Sun Yat Sen Univ, Dept Urol, Guangdong Prov Key Lab Malignant Tumor Epigenet &, Guangdong Prov Clin Res Ctr Urol Dis,Sun Yat Sen, Guangzhou 510120, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
6.Nanjing Med Univ, Dept Immunol, Jiangsu Key Lab Canc Biomarkers Prevent & Treatme, Collaborat Innovat Ctr Personalized Canc Med, 101 Longmian Ave, Nanjing 211166, Peoples R China
推荐引用方式
GB/T 7714		 Li, Ni,Liu, Qiuli,Han, Ying,et al. ARID1A loss induces polymorphonuclear myeloid-derived suppressor cell chemotaxis and promotes prostate cancer progression[J]. NATURE COMMUNICATIONS,2022,13(1):20.
APA Li, Ni.,Liu, Qiuli.,Han, Ying.,Pei, Siyu.,Cheng, Bisheng.,...&Qin, Jun.(2022).ARID1A loss induces polymorphonuclear myeloid-derived suppressor cell chemotaxis and promotes prostate cancer progression.NATURE COMMUNICATIONS,13(1),20.
MLA Li, Ni,et al."ARID1A loss induces polymorphonuclear myeloid-derived suppressor cell chemotaxis and promotes prostate cancer progression".NATURE COMMUNICATIONS 13.1(2022):20.

入库方式： OAI收割

来源：上海药物研究所

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