Prostaglandin E2 Leads to the Acquisition of DNMT3A-Dependent Tolerogenic Functions in Human Myeloid-Derived Suppressor Cells
Javier Rodríguez-Ubreva,
Francesc Català-Moll,
Nataša Obermajer,
Damiana Álvarez-Errico,
Ricardo N. Ramirez,
Carlos Company,
Roser Vento-Tormo,
Gema Moreno-Bueno,
Robert P. Edwards,
Ali Mortazavi,
Pawel Kalinski,
Esteban Ballestar
Affiliations
Javier Rodríguez-Ubreva
Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L’Hospitalet de Llobregat, Barcelona, Spain
Francesc Català-Moll
Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L’Hospitalet de Llobregat, Barcelona, Spain
Nataša Obermajer
Department of Surgery and Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA
Damiana Álvarez-Errico
Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L’Hospitalet de Llobregat, Barcelona, Spain
Ricardo N. Ramirez
Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA
Carlos Company
Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L’Hospitalet de Llobregat, Barcelona, Spain
Roser Vento-Tormo
Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L’Hospitalet de Llobregat, Barcelona, Spain
Gema Moreno-Bueno
Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), IdiPAZ, CIBERONC, 28029 Madrid, Spain
Robert P. Edwards
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
Ali Mortazavi
Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA
Pawel Kalinski
Department of Surgery and Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA
Esteban Ballestar
Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L’Hospitalet de Llobregat, Barcelona, Spain
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.
