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

Sci Adv. 2024 Dec 6;10(49):eadk4851. doi: 10.1126/sciadv.adk4851. Epub 2024 Dec 4.

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.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • DNA Helicases* / genetics
  • DNA Helicases* / metabolism
  • Disease Models, Animal
  • Epigenesis, Genetic*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Interferons / metabolism
  • Mice
  • Mutation*
  • Nuclear Proteins* / genetics
  • Nuclear Proteins* / metabolism
  • Ovarian Neoplasms* / genetics
  • Ovarian Neoplasms* / immunology
  • Ovarian Neoplasms* / pathology
  • Signal Transduction
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism
  • Tumor Microenvironment / immunology

Substances

  • DNA Helicases
  • Transcription Factors
  • Nuclear Proteins
  • SMARCA4 protein, human
  • Interferons
  • Smarca4 protein, mouse