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

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

Author information

1
Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain. Electronic address: jrubreva@idibell.cat.
2
Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain.
3
Department of Surgery and Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
4
Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA.
5
Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), IdiPAZ, CIBERONC, 28029 Madrid, Spain; Fundación MD Anderson International, 28033 Madrid, Spain.
6
Magee-Womens Research Institute Ovarian Cancer Center of Excellence, Peritoneal/Ovarian Cancer Specialty Care Center, and University of Pittsburgh Cancer Institute, University of Pittsburgh, Hillman Cancer Center, Pittsburgh, PA 15213, USA.
7
Department of Surgery and Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Medicine and Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
8
Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain. Electronic address: eballestar@idibell.cat.

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

PMID:
28978469
DOI:
10.1016/j.celrep.2017.09.018
[Indexed for MEDLINE]
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