Prostaglandin E2 (PGE2), an essential homeostatic factor, is also a key mediator of immunopathology in chronic infections and cancer. The impact of PGE2 reflects the balance between its COX2-regulated synthesis and 15-PGDH-driven degradation, and the pattern of expression of PGE2 receptors. PGE2 enhances its own production, but suppresses acute-inflammatory mediators, resulting in its predominance at late/chronic stages of immunity. PGE2 supports activation of dendritic cells, but suppresses their ability to attract naïve, memory- and effector T cells. PGE2 selectively suppresses effector functions of macrophages and neutrophils and the Th1-, CTL- and NK cell-mediated type-1 immunity, but promotes Th2, Th17, and Treg responses. PGE2 modulates chemokine production, inhibiting the attraction of pro-inflammatory cells, while enhancing local accumulation of Treg cells and myeloid-derived suppressor cells. Targeting the production, degradation and responsiveness to PGE2, provides tools to modulate the patterns of immunity in a wide range of diseases, from autoimmunity to cancer.

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Purpose A phase I/II trial was performed to evaluate the safety and immunogenicity of a novel vaccination with α-type 1 polarized dendritic cells (αDC1) loaded with synthetic peptides for glioma-associated antigen (GAA) epitopes and administration of polyinosinic-polycytidylic acid [poly(I:C)] stabilized by lysine and carboxymethylcellulose (poly-ICLC) in HLA-A2+ patients with recurrent malignant gliomas. GAAs for these peptides are EphA2, interleukin (IL)-13 receptor-α2, YKL-40, and gp100. Patients and Methods Twenty-two patients (13 with glioblastoma multiforme [GBM], five with anaplastic astrocytoma [AA], three with anaplastic oligodendroglioma [AO], and one with anaplastic oligoastrocytoma [AOA]) received at least one vaccination, and 19 patients received at least four vaccinations at two αDC1 dose levels (1 × or 3 × 107/dose) at 2-week intervals intranodally. Patients also received twice weekly intramuscular injections of 20 μg/kg poly-ICLC. Patients who demonstrated positive radiologic response or stable disease without major adverse events were allowed to receive booster vaccines. T-lymphocyte responses against GAA epitopes were assessed by enzyme-linked immunosorbent spot and HLA-tetramer assays. Results The regimen was well-tolerated. The first four vaccines induced positive immune responses against at least one of the vaccination-targeted GAAs in peripheral blood mononuclear cells in 58% of patients. Peripheral blood samples demonstrated significant upregulation of type 1 cytokines and chemokines, including interferon-α and CXCL10. Nine (four GBM, two AA, two AO, and one AOA) achieved progression-free status lasting at least 12 months. One patient with recurrent GBM demonstrated sustained complete response. IL-12 production levels by αDC1 positively correlated with time to progression. Conclusion These data support safety, immunogenicity, and preliminary clinical activity of poly-ICLC-boosted αDC1-based vaccines.

Dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) show opposing roles in the immune system. In the present study, we report that the establishment of a positive feedback loop between prostaglandin E 2 (PGE 2 ) and cyclooxygenase 2 (COX2), the key regulator of PGE 2 synthesis, represents the determining factor in redirecting the development of CD1a ؉ DCs to CD14 ؉ CD33 ؉ CD34 ؉ monocytic MDSCs. Exogenous PGE 2 IntroductionDendritic cells (DCs) are key initiators and regulators of immune responses. [1][2][3] Whereas the suppression of endogenous DC function has been shown to contribute to cancer progression, therapeutic targeting of DCs to suppress their function has been shown to be beneficial in mouse models of autoimmunity or transplantation. 4 In contrast to DCs, myeloid-derived suppressor cells (MDSCs) suppress the ability of CD8 ϩ T cells to mediate effective responses against cancer cells, but can be beneficial in controlling autoimmune phenomena or transplantation rejection. [5][6][7] MDSCs express CD34, common myeloid marker CD33, macrophage/DC marker CD11b, and IL-4R␣ (CD124), but lack expression of the lineage (Lin) markers of DCs and other mature myeloid cells. 7,8 Human MDSCs are defined as CD33 ϩ Lin Ϫ HLA-DR Ϫ/low or CD33 ϩ CD14 Ϫ HLA-DR Ϫ , with recent studies demonstrating a CD14 ϩ CD11b ϩ HLA-DR low phenotype of monocytic MDSCs in melanoma, 9 prostate cancer, 10 gastrointestinal malignancies, 11 hepatocellular carcinoma, 12,13 and glioblastoma, 14 in addition to a CD15 ϩ population of neutrophil-related immature MDSCs of similar biologic activity present in the peripheral blood. 7 MDSCs express high levels of immunosuppressive factors such as indoleamine dioxygenase (IDO), 15,16 8 arginase, 17,18 inducible nitric oxide synthase (NOS2), 18 nitric oxide, and reactive oxygen species, 19 and use these molecules to suppress T-cell responses, 20,21 whereas their induction of natural killer cell anergy and reduced cytotoxicity is arginase independent 12 but depends on TGF␤ 1. 22 In addition, PD-L1/B7-H1, which is induced on MDSCs in the tumor microenvironment, 23,24 suppresses antigen-specific immunity by activating regulatory T cells 23 and reduces tumor clearance via enhanced T-cell IL-10 expression and reduced IFN-␥ production. 24 Molecular pathways involved in negative regulation of DC function remain largely unknown; however, they may involve the induction of the myeloid cell-expressed inhibitory immunoglobulinlike transcript receptors ILT-3 and ILT-4, which negatively regulate the activation of DCs, promoting T-cell tolerance. 25,26 The development of functional MDSCs requires the inhibition of immunostimulatory APC development and the concomitant induction of suppressive functions. 5 Such factors as GM-CSF, IL-6, or VEGF promote the expansion of immature myeloid cells (iMCs). 20,[27][28][29] An additional signal is required for the up-regulation of MDSC-associated immunosuppressive factors and for the establishment of their immunosuppressive function. Paradoxically, this signa...