Cell-autonomous inflammation of BRCA1-deficient ovarian cancers drives both tumor-intrinsic immunoreactivity and immune resistance via STING

Cell Rep. 2021 Jul 20;36(3):109412. doi: 10.1016/j.celrep.2021.109412.

Abstract

In this study, we investigate mechanisms leading to inflammation and immunoreactivity in ovarian tumors with homologous recombination deficiency (HRD). BRCA1 loss is found to lead to transcriptional reprogramming in tumor cells and cell-intrinsic inflammation involving type I interferon (IFN) and stimulator of IFN genes (STING). BRCA1-mutated (BRCA1mut) tumors are thus T cell inflamed at baseline. Genetic deletion or methylation of DNA-sensing/IFN genes or CCL5 chemokine is identified as a potential mechanism to attenuate T cell inflammation. Alternatively, in BRCA1mut cancers retaining inflammation, STING upregulates VEGF-A, mediating immune resistance and tumor progression. Tumor-intrinsic STING elimination reduces neoangiogenesis, increases CD8+ T cell infiltration, and reverts therapeutic resistance to dual immune checkpoint blockade (ICB). VEGF-A blockade phenocopies genetic STING loss and synergizes with ICB and/or poly(ADP-ribose) polymerase (PARP) inhibitors to control the outgrowth of Trp53-/-Brca1-/- but not Brca1+/+ ovarian tumors in vivo, offering rational combinatorial therapies for HRD cancers.

Keywords: BRCA1; CTLA-4; DNA sensing; ICB; PARPi; PD-L1; STING; T cells; VEGF-A; angiogenesis; dual immune checkpoint blockade; ovarian cancer; type I IFN.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • BRCA1 Protein / deficiency*
  • BRCA1 Protein / metabolism
  • Cell Line, Tumor
  • Chemokine CCL5 / metabolism
  • Chromatin / metabolism
  • DNA / metabolism
  • DNA Damage
  • Epigenesis, Genetic
  • Female
  • Gene Silencing
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Inflammation / complications
  • Inflammation / immunology
  • Inflammation / pathology*
  • Interferons / metabolism
  • Membrane Proteins / metabolism*
  • Mice, Inbred C57BL
  • Neoplasm Grading
  • Neovascularization, Pathologic / pathology
  • Ovarian Neoplasms / complications
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / immunology*
  • Ovarian Neoplasms / pathology*
  • Protein Serine-Threonine Kinases / metabolism
  • T-Lymphocytes / immunology
  • Transcription, Genetic
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • BRCA1 Protein
  • BRCA1 protein, human
  • Chemokine CCL5
  • Chromatin
  • Immune Checkpoint Inhibitors
  • Membrane Proteins
  • STING1 protein, human
  • Vascular Endothelial Growth Factor A
  • DNA
  • Interferons
  • Protein Serine-Threonine Kinases
  • TBK1 protein, human