MiR21 sensitized B-lymphoma cells to ABT-199 via ICOS/ICOSL-mediated interaction of Treg cells with endothelial cells

J Exp Clin Cancer Res. 2017 Jun 21;36(1):82. doi: 10.1186/s13046-017-0551-z.

Abstract

Background: MicroRNAs (miRs) are involved in tumor progression by regulating tumor cells and tumor microenvironment. MiR21 is overexpressed in diffuse large B-cell lymphoma (DLBCL) and its biological impact on tumor microenvironment remains unclear.

Methods: MiR21 was assessed by quantitative RT-PCR in patients with newly diagnosed DLBCL. The mechanism of action of miR21 on lymphoma progression and tumor angiogenesis was examined in vitro in B-lymphoma cell lines and in vivo in a murine xenograft model.

Results: Serum miR21 was significantly elevated in patients and associated with advanced disease stage, International Prognostic Index indicating intermediate-high and high-risk, and increased tumor angiogenesis. When co-cultured with immune cells and endothelial cells, miR21-overexpressing B-lymphoma cells were resistant to chemotherapeutic agents, but sensitive to Bcl-2 inhibitor ABT-199, irrespective of Bcl-2 expression on lymphoma cells. In both co-culture systems of Bcl-2positive and Bcl-2negative B-lymphoma cells, miR21 induced inducible co-stimulator (ICOS) expression on regulatory T (Treg) cells. Through crosstalking with Treg cells by ICOS ligand (ICOSL), endothelial cells were activated, resulting in stimulation of Bcl-2 expression and vessel formation. ABT-199 directly targeted Bcl-2 on endothelial cells, induced endothelial cell apoptosis and inhibited tumor angiogenesis. In a murine xenograft model established with subcutaneous injection of B-lymphoma cells, ABT-199 particularly retarded the growth of miR21-overexpressing tumors, consistent with the induction of endothelial cell apoptosis and inhibition of tumor angiogenesis.

Conclusions: As a serum oncogenic biomarker of B-cell lymphoma, miR21 indicated B-lymphoma cell sensitivity to ABT-199 via ICOS/ICOSL-mediated interaction of Treg cells with endothelial cells.

Keywords: ABT-199; B-cell lymphoma; Endothelial cells; MicroRNA21; Regulatory T cells; Tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Cell Proliferation
  • Cells, Cultured
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / immunology*
  • Endothelium, Vascular / metabolism
  • Female
  • Humans
  • Inducible T-Cell Co-Stimulator Ligand / metabolism*
  • Inducible T-Cell Co-Stimulator Protein / metabolism*
  • Lymphoma, Large B-Cell, Diffuse / drug therapy
  • Lymphoma, Large B-Cell, Diffuse / genetics
  • Lymphoma, Large B-Cell, Diffuse / immunology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / blood
  • MicroRNAs / genetics*
  • Middle Aged
  • Prognosis
  • Sulfonamides / pharmacology*
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Bridged Bicyclo Compounds, Heterocyclic
  • ICOS protein, human
  • ICOSLG protein, human
  • Inducible T-Cell Co-Stimulator Ligand
  • Inducible T-Cell Co-Stimulator Protein
  • MIRN21 microRNA, human
  • MicroRNAs
  • Sulfonamides
  • venetoclax