Editorial: PGE2‐producing MDSC: a role in tumor progression?

APCs play a fundamental role in the initiation and outcome of the immune response. Depending on their nature and/or properties, they can promote the differentiation and/or expansion of CD4 T cells toward a type 1, type 2, type 17, or regulatory phenotype and promote or suppress CTL proliferation and activity. Seminal work from the group of Gabrilovich [1] clearly demonstrated that TDFs restrain DC maturation and promote the accumulation of MDSCs in tumor-bearing hosts. Indeed, VEGF, GM-CSF, PG, and other factors secreted by tumors promote extramedullary hematopoiesis and lead to MDSC accumulation in the neoplastic bed and in the secondary lymphoid organs. In these sites, MDSCs induce T cell anergy, restrain the effector phase of the CD8 T cell, and can promote antigen-specific Treg proliferation [1, 2] by mechanisms that require arginase and/or NOS expression or TGFand/or ROS production. The appearance of cells with similar properties and phenotype can be obtained from GM-CSF-driven, BM-derived cultures by the addition of tumor-conditioned media [3]. Although in the absence of TDFs, BM precursors differentiate into myeloid DCs; in the presence of conditioned media, CD11c, Gr1 , MHC class II, and F4/80 MDSCs are generated [4]. In this issue, Eruslanov and colleagues [5] suggest that TDFs promote MDSC function and differentiation by inducing the intracellular production of PGE2. PGE2 is one of the best-characterized and studied isoform of eicosanoids that possesses proinflammatory and immunosuppressive properties and that is produced during the course of inflammation following cellular stresses, in response to growth factors, hormones, endotoxin, and inflammatory cytokines or by growing tumors. This eicosanoid is synthesized by COX2, which converts arachidonic acid into PGH2 and PGES1, which isomerizes PGH2 in PGE2, and PGE2 can be catabolized in biologically inactive 15keto-PGs by 15-PGDH and carbonyl reductase or secreted by the transporter MRP4 (Fig. 1). The group of Kusmartsev showed that TDFs induce COX2, PGES1, and MRP4 and down-regulate the expression of 15PGDH in BM-derived MDSCs [5]. These data indicate that MDSCs can actively produce and secrete PGE2. This production and secretion correlate with arginase overexpression, STAT3 and STAT1 phosphorylation, and IL-10 and MIP-2 production, a phenotype typically associated with MDSC suppressive activity. Importantly, COX2 pharmacologic inhibition reverts this suppressive phenotype and partially restores the differentiation of BM cells into myeloid DCs (Fig. 1). PGE2 is a pleiotropic molecule involved in numerous (and sometimes opposite) biological processes, including angiogenesis, apoptosis, inflammation, and immune suppression. Its presence in the tumor microenvironment seems to favor tumor progression. By producing this biological mediator, the role of tumor-associated MDSCs can become more prominent in many neoplastic processes (Fig. 1). Tumor angiogenesis has been correlated with the intratumoral concentration of PGE2. This prostaglandin can influence VEGF mobilization and the incorporation of fibroblast and endothelial cells into a tumor vessel through the binding of EP-2 receptors [6]. Similarly, MDSCs were shown to regulate VEGF bioavailability though MMP9 expression and to promote angiogenesis by being incorporated in tumor vessels. As MDSCs express the PGE2 receptors EP-2 and EP-4, it is possible that they play an even more important role in tumor angiogenesis: in an autocrine manner, by being activated to express MMP9 and in a paracrine manner, by influencing other populations in the tumor stroma [7]. Prevention of apoptosis of neoplastic cells has been associated with PGE2, which in fact, can increase the expression of the antiapoptotic factor BCL-2 and can activate the PI3K/AKT, ERK, EGFR, and cAMP pathways that mediate prosurvival signaling in tumor cells [8]. Thus, it is possible that tumors that are able to recruit and differentiate MDSCs in their stroma