Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain.
Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain.
Cell Rep. 2017 Oct 3;21(1):154-167. doi: 10.1016/j.celrep.2017.09.018.
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.
髓系来源的抑制细胞（MDSCs）和树突状细胞（DCs）来源于共同的祖细胞。肿瘤来源的因子将分化从促进免疫的 DC 重定向到耐受 MDSCs，这是癌症的免疫学标志。事实上，在肿瘤相关条件下（PGE2 或肿瘤细胞条件培养基），从人原代单核细胞中体外分化 DC 会导致 MDSCs 的产生。现在对 MDSC 和 DC 的 DNA 甲基组学进行比较，发现 MDSC 中存在广泛的去甲基化，以及特定的 DNA 甲基化获得和免疫相关基因的抑制，这与 MDSC 中 DNA 甲基转移酶 3A（DNMT3A）水平的增加同时发生。DNMT3A 的下调消除了 MDSC 特异性的过度甲基化，并消除了它们的免疫抑制能力。从卵巢癌患者中分离出的原代 MDSC 与 PGE2 依赖性 DNMT3A 过表达相关，显示出类似的过度甲基化特征。我们的研究将 PGE2 和 DNMT3A 依赖性过度甲基化与抑制性 MDSC 功能联系起来，为治疗干预提供了一个有希望的靶点。
