Site Editor
Joyce F. Liu, MD, MPH
Joyce F. Liu, MD, MPH
Posted: Tuesday, January 21, 2025
According to Dmitriy Zamarin, MD, PhD, of Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, and colleagues, the intracellular mechanisms of immunogenicity in ovarian cancer remain unknown. To elucidate this, these investigators evaluated the changes in cell-extrinsic and -intrinsic immune signaling driven by the loss of SMARCA4—a gene that encodes a protein that plays a crucial role in chromatin remodeling—and published their findings in Science Advances.
“Overall, our findings demonstrate an immunomodulatory role of SMARCA4 and generate rationale for further evaluation of SMARCA4 loss-of-function mutations as predictors of response to immunotherapy,” stated the investigators. “These results [suggest] that modulation of chromatin remodeling through targeting SMARCA4 may serve as a strategy to overcome cancer immune evasion.”
The study authors acquired the ID8-Luciferase, UPK10–green fluorescent protein, OAW28, B16-F10, and Isogenic SMARCA4-knockout murine ovarian cancer cell lines for this analysis. Using ID8, UPK10, and OAW28 models, stable sgSMARCA4 cell lines were created. ID8, UPK10, and B16-F10 single-cell clones were evaluated for SMARCA4 mutations using Sanger sequencing. Total DNA was extracted from murine cell lines and amplified using polymerase chain reaction. ID8 and UPK10 parental cells were treated with 1 μM of the dual BRG1/BRM inhibitor or dual BRG1/BRM proteolysis–targeting chimera/vehicle.
The loss of SMARCA4 in ovarian cancer models elicited an increase in intracellular cancer cell immunogenicity, which was demonstrated by the increased expression of interferon-stimulated genes, upregulation of antigen presentation machinery, and upregulation of long-terminal RNA repeats. Of particular importance, this response was independent of the type I interferon receptor but was observed to be dependent on IRF3, MAVS, and STING signaling.
Additionally, loss of SMARCA4 appeared to change the accessibility of chromatin associated with the induction of interferon-response genes. Of note, both mouse melanoma and ovarian tumors demonstrating a loss of SMARCA4 had increased activation and infiltration of natural killer cells, cytotoxic T cells, and myeloid cells in the tumor microenvironment.
Disclosure: For full disclosures of the study authors, visit www.science.org.
