BRD4 inhibition suppresses PD-L1 expression in triple-negative breast cancer

Exp Cell Res. 2020 Jul 15;392(2):112034. doi: 10.1016/j.yexcr.2020.112034. Epub 2020 Apr 24.

Abstract

Programmed death-ligand 1 (PD-L1) expression on the surface of tumour cells can cause tumour immune evasion. Benefits of combining anti-PD-L1 therapy with nab-paclitaxel in patients with advanced triple-negative breast cancer (TNBC) have been reported. However, some patients cannot tolerate the immune-related adverse effects (irAEs) caused by antibody-based immunotherapy. BRD4 is a member of the bromodomain and extra-terminal domain (BET) family. BRD4 inhibition has shown antitumour effects in many tumours, but its role in TNBC has not been definitively concluded. In particular, the immune regulation of BRD4 in TNBC has been rarely studied. In this study, we used JQ1, a BET inhibitor, and small interfering RNAs (siRNAs) targeting BRD4 to explore the influence of BRD4 on PD-L1 expression in TNBC. The results indicated that BRD4 inhibition suppressed PD-L1 expression and the PD-L1 upregulation induced by interferon-γ (IFN-γ). In the in vivo experiments, we found that JQ1 not only reduced the PD-L1 expression level but also changed the proportions of T lymphocyte subsets in the spleens of tumour-bearing mice, which helped to relieve immunosuppression. Briefly, our study reveals that BRD4 regulates PD-L1 expression and may provide a potential method for blocking the programmed death 1 (PD-1)/PD-L1 immune checkpoint in TNBC.

Keywords: BRD4; Immunosuppression; JQ1; Programmed death-ligand 1; Triple-negative breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Azepines / pharmacology*
  • B7-H1 Antigen / antagonists & inhibitors*
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / metabolism
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Proliferation
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Interferon-gamma / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Middle Aged
  • Prognosis
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Triazoles / pharmacology*
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / metabolism
  • Triple Negative Breast Neoplasms / pathology*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • (+)-JQ1 compound
  • Azepines
  • B7-H1 Antigen
  • BRD4 protein, human
  • Biomarkers, Tumor
  • CD274 protein, human
  • Cell Cycle Proteins
  • Transcription Factors
  • Triazoles
  • Interferon-gamma