Interferon response and epigenetic modulation by SMARCA4 mutations drive ovarian tumor immunogenicity Journal Article
| Authors: | Brodeur, M. N.; Dopeso, H.; Zhu, Y.; Longhini, A. L. F.; Gazzo, A.; Sun, S.; Koche, R. P.; Qu, R.; Rosenberg, L.; Hamard, P. J.; Bykov, Y.; Green, H.; Gusain, L.; Chiappinelli, K. B.; Ozsoy, M. A.; Chui, M. H.; Basili, T.; Gardner, R.; Walderich, S.; DeStanchina, E.; Greenbaum, B.; Gönen, M.; Vabret, N.; Weigelt, B.; Zamarin, D. |
| Article Title: | Interferon response and epigenetic modulation by SMARCA4 mutations drive ovarian tumor immunogenicity |
| Abstract: | Cell-intrinsic mechanisms of immunogenicity in ovarian cancer (OC) are not well understood. Damaging mutations in the SWI/SNF chromatin remodeling complex, such as SMARCA4 (BRG1), are associated with improved response to immune checkpoint blockade; however, the mechanism by which this occurs is unclear. We found that SMARCA4 loss in OC models resulted in increased cancer cell–intrinsic immunogenicity, characterized by up-regulation of long-terminal RNA repeats, increased expression of interferon-stimulated genes, and up-regulation of antigen presentation machinery. Notably, this response was dependent on STING, MAVS, and IRF3 signaling but was independent of the type I interferon receptor. Mouse ovarian and melanoma tumors with SMARCA4 loss demonstrated increased infiltration and activation of cytotoxic T cells, NK cells, and myeloid cells in the tumor microenvironment. These results were recapitulated in BRG1 inhibitor–treated SMARCA4-proficient tumor models, suggesting that modulation of chromatin remodeling through targeting SMARCA4 may serve as a strategy to overcome cancer immune evasion. Copyright © 2024 The Authors, some rights reserved |
| Keywords: | signal transduction; genetics; mutation; interferon; ovarian neoplasms; mouse; animal; metabolism; animals; mice; gene expression; nuclear protein; transcription factor; pathology; cell line, tumor; transcription factors; nuclear proteins; disease model; gene expression regulation; gene expression regulation, neoplastic; immunology; epigenetics; epigenesis, genetic; immunogenicity; ovary tumor; tumor cell line; up-regulation; disease models, animal; genetic epigenesis; dna helicases; dna helicase; cancer cells; ovarian cancers; t-cells; cell signaling; tumor microenvironment; chromatin remodeling complex; interferons; cancer models; humans; human; female; swi-snf; smarca4 protein, human; interferon response; smarca4 protein, mouse; intrinsic mechanisms; ovarian tumor |
| Journal Title: | Science Advances |
| Volume: | 10 |
| Issue: | 49 |
| ISSN: | 2375-2548 |
| Publisher: | Amer Assoc Advancement Science |
| Date Published: | 2024-12-06 |
| Start Page: | eadk4851 |
| Language: | English |
| DOI: | 10.1126/sciadv.adk4851 |
| PUBMED: | 39630912 |
| PROVIDER: | scopus |
| PMCID: | PMC11616711 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is Dmitriy Zamarin -- Source: Scopus |
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