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
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
