Prostaglandin E2 Leads to the Acquisition of DNMT3A-Dependent Tolerogenic Functions in Human Myeloid-Derived Suppressor Cells

Cell Rep. 2017 Oct 3;21(1):154-167. doi: 10.1016/j.celrep.2017.09.018.

Abstract

Myeloid-derived suppressor cells (MDSCs) and dendritic cells (DCs) arise from common progenitors. Tumor-derived factors redirect differentiation from immune-promoting DCs to tolerogenic MDSCs, an immunological hallmark of cancer. Indeed, in vitro differentiation of DCs from human primary monocytes results in the generation of MDSCs under tumor-associated conditions (PGE2 or tumor cell-conditioned media). Comparison of MDSC and DC DNA methylomes now reveals extensive demethylation with specific gains of DNA methylation and repression of immunogenic-associated genes occurring in MDSCs specifically, concomitant with increased DNA methyltransferase 3A (DNMT3A) levels. DNMT3A downregulation erases MDSC-specific hypermethylation, and it abolishes their immunosuppressive capacity. Primary MDSCs isolated from ovarian cancer patients display a similar hypermethylation signature in connection with PGE2-dependent DNMT3A overexpression. Our study links PGE2- and DNMT3A-dependent hypermethylation with immunosuppressive MDSC functions, providing a promising target for therapeutic intervention.

Keywords: DNA methylation; DNMT3A; epigenetics; myeloid differentiation; myeloid-derived suppressor cells; ovarian carcinoma; prostaglandin E2; tolerogenesis; tolerogenic.

MeSH terms

  • CD11b Antigen / genetics
  • CD11b Antigen / immunology
  • Cell Differentiation / drug effects
  • Cell Lineage / drug effects
  • Cell Lineage / immunology
  • Chemokine CCL22 / genetics
  • Chemokine CCL22 / immunology
  • Core Binding Factor Alpha 2 Subunit / genetics
  • Core Binding Factor Alpha 2 Subunit / immunology
  • Culture Media, Conditioned / pharmacology
  • Cyclic AMP Response Element Modulator / genetics
  • Cyclic AMP Response Element Modulator / immunology
  • DNA (Cytosine-5-)-Methyltransferases / genetics*
  • DNA (Cytosine-5-)-Methyltransferases / immunology
  • DNA Methylation
  • Dinoprostone / pharmacology*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immune Tolerance*
  • Monocytes / drug effects
  • Monocytes / immunology
  • Multigene Family
  • Myeloid-Derived Suppressor Cells / drug effects*
  • Myeloid-Derived Suppressor Cells / immunology
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / immunology
  • Ovarian Neoplasms / pathology
  • Primary Cell Culture

Substances

  • CCL22 protein, human
  • CD11b Antigen
  • CREM protein, human
  • Chemokine CCL22
  • Core Binding Factor Alpha 2 Subunit
  • Culture Media, Conditioned
  • ITGAM protein, human
  • RUNX1 protein, human
  • Cyclic AMP Response Element Modulator
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3A
  • Dinoprostone