BET protein targeting suppresses the PD-1/PD-L1 pathway in triple-negative breast cancer and elicits anti-tumor immune response

Cancer Lett. 2019 Nov 28;465:45-58. doi: 10.1016/j.canlet.2019.08.013. Epub 2019 Aug 29.

Abstract

Therapeutic strategies aiming to leverage anti-tumor immunity are being intensively investigated as they show promising results in cancer therapy. The PD-1/PD-L1 pathway constitutes an important target to restore functional anti-tumor immune response. Here, we report that BET protein inhibition suppresses PD-1/PD-L1 in triple-negative breast cancer. BET proteins control PD-1 expression in T cells, and PD-L1 in breast cancer cell models. BET protein targeting reduces T cell-derived interferon-γ production and signaling, thereby suppressing PD-L1 induction in breast cancer cells. Moreover, BET protein inhibition improves tumor cell-specific T cell cytotoxic function. Overall, we demonstrate that BET protein targeting represents a promising strategy to overcome tumor-reactive T cell exhaustion and improve anti-tumor immune responses, by reducing the PD-1/PD-L1 axis in triple-negative breast cancer.

Keywords: BET proteins; Immune exhaustion; Immunotherapy; PD-1; PD-L1; Triple-negative breast cancer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Azepines / pharmacology*
  • B7-H1 Antigen / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Coculture Techniques
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Interferon-gamma / metabolism
  • Programmed Cell Death 1 Receptor / metabolism*
  • Proteins / antagonists & inhibitors*
  • Signal Transduction / drug effects
  • T-Lymphocytes / immunology
  • Triazoles / pharmacology*
  • Triple Negative Breast Neoplasms / drug therapy
  • Triple Negative Breast Neoplasms / immunology
  • Triple Negative Breast Neoplasms / metabolism*

Substances

  • (+)-JQ1 compound
  • Azepines
  • B7-H1 Antigen
  • CD274 protein, human
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Proteins
  • Triazoles
  • bromodomain and extra-terminal domain protein, human
  • Interferon-gamma