Interferon response and epigenetic modulation by SMARCA4 mutations drive ovarian tumor immunogenicity

Authors

• Melica Nourmoussavi Brodeur, Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
• Higinio Dopeso, Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
• Yingjie Zhu, Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
• Ana Leda Longhini, Flow Cytometry Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
• Andrea Gazzo, Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
• Siyu Sun, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
• Richard P. Koche, Center for Epigenetic Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
• Rui Qu, Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
• Laura Rosenberg, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
• Pierre-Jacques Hamard, Center for Epigenetic Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
• Yonina Bykov, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
• Hunter Green, Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
• Laxmi Gusain, Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
• Katherine B. Chiappinelli, Department of Microbiology, Immunology and Tropical Medicine, The GW Cancer Center, The George Washington University, Washington, DC, USA.
• Melih Arda Ozsoy, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
• M Herman Chui, Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
• Thais Basili, Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
• Rui Gardner, Flow Cytometry Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
• Sven Walderich, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
• Elisa DeStanchina, Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
• Benjamin Greenbaum, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
• Mithat Gönen, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
• Nicolas Vabret, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
• Britta Weigelt, Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
• Dmitriy Zamarin, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Document Type

Journal Article

Publication Date

12-6-2024

Journal

Science advances

Volume

10

Issue

49

DOI

10.1126/sciadv.adk4851

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.

APA Citation

Brodeur, Melica Nourmoussavi; Dopeso, Higinio; Zhu, Yingjie; Longhini, Ana Leda; Gazzo, Andrea; Sun, Siyu; Koche, Richard P.; Qu, Rui; Rosenberg, Laura; Hamard, Pierre-Jacques; Bykov, Yonina; Green, Hunter; Gusain, Laxmi; Chiappinelli, Katherine B.; Ozsoy, Melih Arda; Chui, M Herman; Basili, Thais; Gardner, Rui; Walderich, Sven; DeStanchina, Elisa; Greenbaum, Benjamin; Gönen, Mithat; Vabret, Nicolas; Weigelt, Britta; and Zamarin, Dmitriy, "Interferon response and epigenetic modulation by SMARCA4 mutations drive ovarian tumor immunogenicity" (2024). GW Authored Works. Paper 6192.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/6192

Department

Microbiology, Immunology, and Tropical Medicine