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Prostaglandin E2 produced by myeloid-derived suppressive cells induces cancer stem cells in uterine cervical cancer.

ABSTRACT: Myeloid-derived suppressor cells (MDSCs) enhance tumor progression by suppressing tumor-specific T cell responses, stimulating tumor angiogenesis, or promoting tumor cell metastasis. However, the biology of MDSCs have not been fully investigated. In the current study, we investigated the role of MDSCs in inducing cancer stem-like cells and explored a clinically feasible approach for targeting MDSCs-mediated cancer stem-like cells induction. In vitro and in vivo experiments revealed that MDSCs induced by tumor-derived G-CSF enhanced the stemness of cervical cancer cells by producing Prostaglandin E2 (PGE2). We also demonstrated that anti-Gr-1 neutralizing antibody or celecoxib inhibited the induction of cancer stem-like cells and enhanced the efficacy of cisplatin in cervical cancer. In clinical samples, MDSCs, PGE2, and CSCs had positive correlations. In conclusion, G-CSF-induced MDSCs enhance the stemness of uterine cervical cancer cells by producing PGE2. Targeting MDSCs or PGE2 might be a reasonable strategy for enhancing the efficacies of treatments.?.

SUBMITTER: Kuroda H

PROVIDER: S-EPMC6284736 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Prostaglandin E2 produced by myeloid-derived suppressive cells induces cancer stem cells in uterine cervical cancer.

Kuroda Hiromasa H Mabuchi Seiji S Yokoi Eriko E Komura Naoko N Kozasa Katsumi K Matsumoto Yuri Y Kawano Mahiru M Takahashi Ryoko R Sasano Tomoyuki T Shimura Kotaro K Kodama Michiko M Hashimoto Kae K Sawada Kenjiro K Morii Eiichi E Kimura Tadashi T

Oncotarget 20181120 91

Myeloid-derived suppressor cells (MDSCs) enhance tumor progression by suppressing tumor-specific T cell responses, stimulating tumor angiogenesis, or promoting tumor cell metastasis. However, the biology of MDSCs have not been fully investigated. In the current study, we investigated the role of MDSCs in inducing cancer stem-like cells and explored a clinically feasible approach for targeting MDSCs-mediated cancer stem-like cells induction. <i>In vitro</i> and <i>in vivo</i> experiments revealed ...[more]

PMID: 30555631

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Project description:IntroductionEfferocytosis is a crucial process by which apoptotic cells are cleared by phagocytes, maintaining immune tolerance to self in the absence of inflammation. Peripheral tolerance, lost in autoimmune processes, may be restored by the administration of autologous dendritic cells loaded with islet apoptotic cells in experimental type 1 diabetes.ObjectiveTo evaluate tolerogenic properties in dendritic cells induced by the clearance of apoptotic islet cells, thus explaining the re-establishment of tolerance in a context of autoimmunity.MethodsBone marrow derived dendritic cells from non-obese diabetic mice, a model of autoimmune diabetes, were generated and pulsed with islet apoptotic cells. The ability of these cells to induce autologous T cell proliferation and to suppress mature dendritic cell function was assessed, together with cytokine production. Microarray experiments were performed using dendritic cells to identify differentially expressed genes after efferocytosis.ResultsMolecular and functional changes in dendritic cells after the capture of apoptotic cells were observed. 1) Impaired ability of dendritic cells to stimulate autologous T cell proliferation after the capture of apoptotic cells even after proinflammatory stimuli, with a cytokine profile typical for immature dendritic cells. 2) Suppressive ability of mature dendritic cell function. 3) Microarray-based gene expression profiling of dendritic cells showed differential expression of genes involved in antigen processing and presentation after efferocytosis. 4) Prostaglandin E2 increased production was responsible for immunosuppressive mechanism of dendritic cells after the capture of apoptotic cells.ConclusionsThe tolerogenic behaviour of dendritic cells after islet cells efferocytosis points to a mechanism of silencing potential autoreactive T cells in the microenvironment of autoimmunity. Our results suggest that dendritic cells may be programmed to induce specific immune tolerance using apoptotic cells; this is a viable strategy for a variety of autoimmune diseases.

Project description:: Human mesenchymal stem cells (hMSCs) are being increasingly pursued as potential therapies for immune-mediated conditions, including multiple sclerosis. Although they can suppress human Th1 responses, they reportedly can reciprocally enhance human Th17 responses. Here, we investigated the mechanisms underlying the capacity of hMSCs to modulate human Th1 and Th17 responses. Human adult bone marrow-derived MSCs were isolated, and their purity and differentiation capacity were confirmed. Human venous peripheral blood mononuclear cells (PBMC) were activated, alone, together with hMSC, or in the presence of hMSC-derived supernatants (sups). Cytokine expression by CD4+ T-cell subsets (intracellular staining by fluorescence-activated cell sorting) and secreted cytokines (enzyme-linked immunosorbent assay) were then quantified. The contribution of prostaglandin E2 (PGE2) as well as of myeloid cells to the hMSC-mediated regulation of T-cell responses was investigated by selective depletion of PGE2 from the hMSC sups (anti-PGE2 beads) and by the selective removal of CD14+ cells from the PBMC (magnetic-activated cell sorting separation). Human MSC-secreted products could reciprocally induce interleukin-17 expression while decreasing interferon-γ expression by human CD4+ T cells, both in coculture and through soluble products. Pre-exposure of hMSCs to IL-1β accentuated their capacity to reciprocally regulate Th1 and Th17 responses. Human MSCs secreted high levels of PGE2, which correlated with their capacity to regulate the T-cell responses. Selective removal of PGE2 from the hMSC supernatants abrogated the impact of hMSC on the T cells. Selective removal of CD14+ cells from the PBMCs also limited the capacity of hMSC-secreted PGE2 to affect T-cell responses. Our discovery of a novel PGE2-dependent and myeloid cell-mediated mechanism by which human MSCs can reciprocally induce human Th17 while suppressing Th1 responses has implications for the use of, as well as monitoring of, MSCs as a potential therapeutic for patients with multiple sclerosis and other immune-mediated diseases.SignificanceAlthough animal studies have generated a growing interest in the anti-inflammatory potential of mesenchymal stem cells (MSCs) for the treatment of autoimmune diseases, MSCs possess the capacity to both limit and promote immune responses. Yet relatively little is known about human-MSC modulation of human disease-implicated T-cell responses, or the mechanisms underlying such modulation. The current study reveals a novel prostaglandin E2-dependent and myeloid cell-mediated mechanism by which human MSCs can reciprocally regulate human Th17 and Th1 responses, with implications for the use of MSCs as a potential therapeutic for patients with multiple sclerosis and other immune-mediated diseases.

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Prostaglandin E2 produced by myeloid-derived suppressive cells induces cancer stem cells in uterine cervical cancer.

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Prostaglandin E2 produced by myeloid-derived suppressive cells induces cancer stem cells in uterine cervical cancer.

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