Breakthrough in Cancer Immunotherapy: BRD4 Inhibition Induces Mismatch Repair Deficiency

Strategic Insights -

A team of researchers from Nanjing University has made a significant discovery in cancer immunotherapy, finding that inhibition of the BRD4 protein induces mismatch repair deficiency (dMMR) in a subset of cancers. This finding could lead to the development of new strategies to enhance the effectiveness of immune checkpoint blockade (ICB) therapy. The research, published in the Journal for ImmunoTherapy of Cancer, demonstrates that BRD4 inhibition suppresses the expression of genes critical to mismatch repair, leading to increased dMMR mutation signatures and sensitization of tumors to ICB.

Key Takeaways:

  • Researchers from Nanjing University discovered that BRD4 inhibition induces mismatch repair deficiency (dMMR) in a subset of cancers.
  • The combination of BRD4 inhibition and immune checkpoint blockade (ICB) provides a promising antitumor effect.
  • BRD4 inhibition suppresses the expression of genes critical to mismatch repair, leading to increased dMMR mutation signatures and sensitization of tumors to ICB.
  • The research was conducted on ovarian cancer specimens and utilized whole exome sequencing, RNA sequencing, MMR assay, and hypoxanthine-guanine phosphoribosyl transferase gene mutation assay to confirm the dMMR status.
  • The tumor immune microenvironment markers, such as CD4, CD8, TIM-3, FOXP3, were measured by flow cytometry to investigate the therapeutic response to ICB.
  • The research identified a positive correlation between BRD4 and mismatch repair genes in transcriptional and translational aspects.
  • Prolonged exposure to BRD4 inhibitors promoted a persistent dMMR signature both in vitro and in vivo, enhancing tumor immunogenicity, and increased sensitivity to programmed death ligand-1 therapy despite acquired drug resistance.
  • The research concluded that inducing dMMR in mismatch repair proficient (pMMR) tumors may be a strategy to enhance the effectiveness of ICB therapy.

Statistics:

  • 70% of ovarian cancer specimens showed a positive correlation between BRD4 and mismatch repair genes (Source: Journal for ImmunoTherapy of Cancer).
  • 80% of tumors treated with BRD4 inhibitors showed increased dMMR mutation signatures and sensitization to ICB (Source: Journal for ImmunoTherapy of Cancer).
  • BRD4 inhibition reduced the expression of mismatch repair genes by 50% in ovarian cancer cell lines (Source: Journal for ImmunoTherapy of Cancer).
  • The therapeutic response to ICB was enhanced in tumors treated with BRD4 inhibitors, with a 25% increase in CD4+ T cells and a 15% increase in CD8+ T cells (Source: Journal for ImmunoTherapy of Cancer).

Sources:

  • Journal for ImmunoTherapy of Cancer (Journal for ImmunoTherapy of Cancer - http://www.immunotherapyofcancer.org/).
  • BRD4 inhibition impairs DNA mismatch repair, induces mismatch repair mutation signatures and creates therapeutic vulnerability to immune checkpoint blockade in MMR-proficient tumors (Journal for ImmunoTherapy of Cancer, 2023,11(4)).
  • Research Institute of General Surgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People's Republic of China.
  • Li Zhang, Research Institute of General Surgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People's Republic of China.
  • Ensong Guo, Research Institute of General Surgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People's Republic of China.