Epigenetic driver mutations in ARID1A shape cancer immune phenotype and immunotherapy Journal Article
| Authors: | Li, J.; Wang, W.; Zhang, Y.; Cieślik, M.; Guo, J.; Tan, M.; Green, M. D.; Wang, W.; Lin, H.; Li, W.; Wei, S.; Zhou, J.; Li, G.; Jing, X.; Vatan, L.; Zhao, L.; Bitler, B.; Zhang, R.; Cho, K. R.; Dou, Y.; Kryczek, I.; Chan, T. A.; Huntsman, D.; Chinnaiyan, A. M.; Zou, W. |
| Article Title: | Epigenetic driver mutations in ARID1A shape cancer immune phenotype and immunotherapy |
| Abstract: | Whether mutations in cancer driver genes directly affect cancer immune phenotype and T cell immunity remains a standing question. ARID1A is a core member of the polymorphic BRG/BRM-associated factor chromatin remodeling complex. ARID1A mutations occur in human cancers and drive cancer development. Here, we studied the molecular, cellular, and clinical impact of ARID1A aberrations on cancer immunity. We demonstrated that ARID1A aberrations resulted in limited chromatin accessibility to IFN-responsive genes, impaired IFN gene expression, anemic T cell tumor infiltration, poor tumor immunity, and shortened host survival in many human cancer histologies and in murine cancer models. Impaired IFN signaling was associated with poor immunotherapy response. Mechanistically, ARID1A interacted with EZH2 via its carboxyl terminal and antagonized EZH2-mediated IFN responsiveness. Thus, the interaction between ARID1A and EZH2 defines cancer IFN responsiveness and immune evasion. Our work indicates that cancer epigenetic driver mutations can shape cancer immune phenotype and immunotherapy. Copyright: © 2020, American Society for Clinical Investigation. |
| Keywords: | controlled study; gene mutation; human cell; nonhuman; cd8+ t lymphocyte; tumor associated leukocyte; mouse; phenotype; gene; cancer immunotherapy; gene expression; carboxy terminal sequence; animal experiment; animal model; histology; granzyme b; cellular immunity; epigenetics; cancer infiltration; cytotoxic t lymphocyte; tumor immunity; perforin; ovary metastasis; gamma interferon inducible protein 10; cd3+ t lymphocyte; beta interferon; chromatin assembly and disassembly; cxcl9 chemokine; tumor microenvironment; transcription factor ezh2; immune evasion; gene expression level; cxcl11 chemokine; polycomb repressive complex 2; arid1a gene; interferon regulatory factor 1; human; female; priority journal; article; ovarian clear cell carcinoma cell line |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 130 |
| Issue: | 5 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2020-05-01 |
| Start Page: | 2712 |
| End Page: | 2726 |
| Language: | English |
| DOI: | 10.1172/jci134402 |
| PUBMED: | 32027624 |
| PROVIDER: | scopus |
| PMCID: | PMC7190935 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
