Interferon response and epigenetic modulation by <i>SMARCA4</i> mutations drive ovarian tumor immunogenicity
Cell-intrinsic mechanisms of immunogenicity in ovarian cancer (OC) are not well understood. Damaging mutations in the SWI/SNF chromatin remodeling complex, such as <i>SMARCA4</i> (BRG1), are associated with improved response to immune checkpoint blockade; however, the mechanism by which this occurs is unclear. We found that <i>SMARCA4</i> 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 <i>SMARCA4</i> 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 <i>SMARCA4-</i>proficient tumor models, suggesting that modulation of chromatin remodeling through targeting <i>SMARCA4</i> may serve as a strategy to overcome cancer immune evasion.
Authors
- Elisa de Stanchina (ORCID: https://orcid.org/0000-0002-3873-315X)
- Ana Leda F. Longhini (ORCID: https://orcid.org/0000-0002-2817-725X)
- Melih Arda Ozsoy (ORCID: https://orcid.org/0009-0000-8234-0954)
- M. Herman Chui (ORCID: https://orcid.org/0000-0002-7220-3996)
- Siyu Sun (ORCID: https://orcid.org/0000-0001-8461-9609)
- Dmitriy Zamarin (ORCID: https://orcid.org/0000-0002-0094-0161)
- Laxmi Gusain (ORCID: https://orcid.org/0000-0002-7140-5350)
- Rui Gardner (ORCID: https://orcid.org/0000-0002-7270-5136)
- Melica Nourmoussavi Brodeur (ORCID: https://orcid.org/0000-0002-7595-0313)
- Sven Walderich (ORCID: https://orcid.org/0000-0003-3671-3494)
- Andrea Gazzo (ORCID: https://orcid.org/0009-0009-9282-4667)
- Pierre-Jacques Hamard (ORCID: https://orcid.org/0000-0002-2484-6161)
- Britta Weigelt (ORCID: https://orcid.org/0000-0001-9927-1270)
- Katherine B. Chiappinelli (ORCID: https://orcid.org/0000-0001-9241-9105)
- Mithat Gönen (ORCID: https://orcid.org/0000-0001-8683-8477)
- Benjamin D. Greenbaum (ORCID: https://orcid.org/0000-0001-6153-8793)
- Nicolas Vabret (ORCID: https://orcid.org/0000-0002-0846-1819)
- Rui Qu (ORCID: https://orcid.org/0009-0009-1185-9076)
- Richard P. Koche (ORCID: https://orcid.org/0000-0002-6820-5083)
- Yonina Bykov (ORCID: https://orcid.org/0000-0002-0834-0953)
- Higinio Dopeso (ORCID: https://orcid.org/0000-0003-0060-1861)
- Thais Basili (ORCID: https://orcid.org/0000-0003-3216-3544)
- Yingjie Zhu (ORCID: https://orcid.org/0000-0003-1849-6019)
- Hunter Green (ORCID: https://orcid.org/0009-0002-3944-6803)
- Laura Rosenberg (ORCID: https://orcid.org/0000-0003-3353-6402)
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- University of California, San Francisco (US)
- George Washington University (US)
- Cornell University (US)
- Weill Cornell Medicine (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Science Advances
- Published
- 2024-12-04
- DOI
- https://doi.org/10.1126/sciadv.adk4851
- Citations
- 6
- Primary Topic
- Chromatin Remodeling and Cancer
- Type
- article
- Field-Weighted Citation Impact
- 1.40