| First Author | Li N | Year | 2022 |
| Journal | Nat Commun | Volume | 13 |
| Issue | 1 | Pages | 7281 |
| PubMed ID | 36435834 | Mgi Jnum | J:331706 |
| Mgi Id | MGI:7397703 | Doi | 10.1038/s41467-022-34871-9 |
| Citation | Li N, et al. (2022) ARID1A loss induces polymorphonuclear myeloid-derived suppressor cell chemotaxis and promotes prostate cancer progression. Nat Commun 13(1):7281 |
| abstractText | 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 IKKbeta 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 IKKbeta 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-kappaB signaling, and thereby unleashes CXCR2 ligand-mediated MDSC chemotaxis. Importantly, our results support the therapeutic strategy of anti-NF-kappaB antibody or targeting CXCR2 combined with ICB for advanced PCa. Together, our findings highlight that the IKKbeta/ARID1A/NF-kappaB feedback axis integrates inflammation and immunosuppression to promote PCa progression. |
