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

Publication date: 3 October 2017
Source:Cell Reports, Volume 21, Issue 1
Author(s): 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
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.

Graphical abstract

Teaser

Rodríguez-Ubreva et al. find that inflammatory factors, such as prostaglandin E2, that are able to redirect the differentiation of precursor myeloid cells toward tolerogenic myeloid-derived suppressor cells (MDSCs) also impose a DNMT3A-dependent fingerprint in myeloid genes that leads to the acquisition of suppressive properties.


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