53BP1 loss elicits cGAS-STING-dependent antitumor immunity in ovarian and pancreatic cancer

Nat Commun. 2024 Aug 6;15(1):6676. doi: 10.1038/s41467-024-50999-2.

Abstract

53BP1 nucleates the anti-end resection machinery at DNA double-strand breaks, thereby countering BRCA1 activity. Loss of 53BP1 leads to DNA end processing and homologous recombination in BRCA1-deficient cells. Consequently, BRCA1-mutant tumors, typically sensitive to PARP inhibitors (PARPi), become resistant in the absence of 53BP1. Here, we demonstrate that the 'leaky' DNA end resection in the absence of 53BP1 results in increased micronuclei and cytoplasmic double-stranded DNA, leading to activation of the cGAS-STING pathway and pro-inflammatory signaling. This enhances CD8+ T cell infiltration, activates macrophages and natural killer cells, and impedes tumor growth. Loss of 53BP1 correlates with a response to immune checkpoint blockade (ICB) and improved overall survival. Immunohistochemical assessment of 53BP1 in two malignancies, high grade serous ovarian cancer and pancreatic ductal adenocarcinoma, which are refractory to ICBs, reveals that lower 53BP1 levels correlate with an increased adaptive and innate immune response. Finally, BRCA1-deficient tumors that develop resistance to PARPi due to the loss of 53BP1 are susceptible to ICB. Therefore, we conclude that 53BP1 is critical for tumor immunogenicity and underpins the response to ICB. Our results support including 53BP1 expression as an exploratory biomarker in ICB trials for malignancies typically refractory to immunotherapy.

MeSH terms

  • Animals
  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism
  • CD8-Positive T-Lymphocytes / immunology
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / immunology
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • DNA Breaks, Double-Stranded
  • Female
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immune Checkpoint Inhibitors / therapeutic use
  • Immunity, Innate
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism
  • Membrane Proteins* / genetics
  • Membrane Proteins* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nucleotidyltransferases* / genetics
  • Nucleotidyltransferases* / metabolism
  • Ovarian Neoplasms* / genetics
  • Ovarian Neoplasms* / immunology
  • Ovarian Neoplasms* / metabolism
  • Ovarian Neoplasms* / pathology
  • Pancreatic Neoplasms* / genetics
  • Pancreatic Neoplasms* / immunology
  • Pancreatic Neoplasms* / metabolism
  • Pancreatic Neoplasms* / pathology
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use
  • Signal Transduction
  • Tumor Suppressor p53-Binding Protein 1* / genetics
  • Tumor Suppressor p53-Binding Protein 1* / metabolism

Substances

  • Tumor Suppressor p53-Binding Protein 1
  • Nucleotidyltransferases
  • Membrane Proteins
  • TP53BP1 protein, human
  • STING1 protein, human
  • cGAS protein, human
  • BRCA1 Protein
  • Immune Checkpoint Inhibitors
  • Poly(ADP-ribose) Polymerase Inhibitors
  • cGAS protein, mouse
  • Trp53bp1 protein, mouse
  • Sting1 protein, mouse