Apigenin inhibits the inducible expression of programmed death ligand 1 by human and mouse mammary carcinoma cells

Cancer Lett. 2016 Oct 1;380(2):424-33. doi: 10.1016/j.canlet.2016.06.023. Epub 2016 Jul 1.

Abstract

Programmed death ligand 1 (PD-L1) is expressed by many cancer cell types, as well as by activated T cells and antigen-presenting cells. Constitutive and inducible PD-L1 expression contributes to immune evasion by breast cancer (BC) cells. We show here that the dietary phytochemical apigenin inhibited interferon (IFN)-γ-induced PD-L1 upregulation by triple-negative MDA-MB-468 BC cells, HER2(+) SK-BR-3 BC cells, and 4T1 mouse mammary carcinoma cells, as well as human mammary epithelial cells, but did not affect constitutive PD-L1 expression by triple-negative MDA-MB-231 BC cells. IFN-β-induced expression of PD-L1 by MDA-MB-468 cells was also inhibited by apigenin. In addition, luteolin, the major metabolite of apigenin, inhibited IFN-γ-induced PD-L1 expression by MDA-MB-468 cells. Apigenin-mediated inhibition of IFN-γ-induced PD-L1 expression by MDA-MB-468 and 4T1 cells was associated with reduced phosphorylation of STAT1, which was early and transient at Tyr701 and sustained at Ser727. Apigenin-mediated inhibition of IFN-γ-induced PD-L1 expression by MDA-MB-468 cells also increased proliferation and interleukin-2 synthesis by PD-1-expressing Jurkat T cells that were co-cultured with MDA-MB-468 cells. Apigenin therefore has the potential to increase the vulnerability of BC cells to T cell-mediated anti-tumor immune responses.

Keywords: Breast cancer; Flavonoid; Immune evasion; PD-L1; Signal transduction.

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apigenin / pharmacology*
  • B7-H1 Antigen / metabolism*
  • Biomarkers, Tumor / metabolism
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Proliferation / drug effects
  • Coculture Techniques
  • Female
  • Humans
  • Interferon-beta / pharmacology
  • Interferon-gamma / pharmacology
  • Jurkat Cells
  • Luteolin / pharmacology
  • Lymphocyte Activation / drug effects
  • Mice
  • Phosphorylation
  • Receptor, ErbB-2 / metabolism
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / metabolism
  • Triple Negative Breast Neoplasms / pathology

Substances

  • Antineoplastic Agents, Phytogenic
  • B7-H1 Antigen
  • Biomarkers, Tumor
  • CD274 protein, human
  • Cd274 protein, mouse
  • IFNG protein, human
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Stat1 protein, mouse
  • Interferon-beta
  • Apigenin
  • Interferon-gamma
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Luteolin

Grant support