Calcium/Calmodulin Dependent Protein Kinase Kinase 2 Regulates the Expansion of Tumor-Induced Myeloid-Derived Suppressor Cells.

Myeloid-derived suppressor cells (MDSCs) are a hetero geneous group of cells, which can suppress the immune response, promote tumor progression and impair the efficacy of immunotherapies. Consequently, the pharmacological targeting of MDSC is emerging as a new immunotherapeutic strategy to stimulate the natural anti-tumor immune response and potentiate the efficacy of immunotherapies. Herein, we leveraged genetically modified models and a small molecule inhibitor to validate Calcium-Calmodulin Kinase Kinase 2 (CaMKK2) as a druggable target to control MDSC accumulation in tumor-bearing mice. The results indicated that deletion of CaMKK2 in the host attenuated the growth of engrafted tumor cells, and this phenomenon was associated with increased antitumor T cell response and decreased accumulation of MDSC. The adoptive transfer of MDSC was sufficient to restore the ability of the tumor to grow in Camkk2-/- mice, confirming the key role of MDSC in the mechanism of tumor rejection. In vitro studies indicated that blocking of CaMKK2 is sufficient to impair the yield of MDSC. Surprisingly, MDSC generated from Camkk2-/- bone marrow cells also showed a higher ability to terminally differentiate toward more immunogenic cell types (e.g inflammatory macrophages and dendritic cells) compared to wild type (WT). Higher intracellular levels of reactive oxygen species (ROS) accumulated in Camkk2-/- MDSC, increasing their susceptibility to apoptosis and promoting their terminal differentiation toward more mature myeloid cells. Mechanistic studies indicated that AMP-activated protein kinase (AMPK), which is a known CaMKK2 proximal target controlling the oxidative stress response, fine-tunes ROS accumulation in MDSC. Accordingly, failure to activate the CaMKK2-AMPK axis can account for the elevated ROS levels in Camkk2-/- MDSC. These results highlight CaMKK2 as an important regulator of the MDSC lifecycle, identifying this kinase as a new druggable target to restrain MDSC expansion and enhance the efficacy of anti-tumor immunotherapy.

Myeloid-derived suppressor cells as immunosuppressive regulators and therapeutic targets in cancer.

Myeloid-derived suppressor cells (MDSCs) are a heterogenic population of immature myeloid cells with immunosuppressive effects, which undergo massive expansion during tumor progression. These cells not only support immune escape directly but also promote tumor invasion via various non-immunological activities. Besides, this group of cells are proved to impair the efficiency of current antitumor strategies such as chemotherapy, radiotherapy, and immunotherapy. Therefore, MDSCs are considered as potential therapeutic targets for cancer therapy. Treatment strategies targeting MDSCs have shown promising outcomes in both preclinical studies and clinical trials when administrated alone, or in combination with other anticancer therapies. In this review, we shed new light on recent advances in the biological characteristics and immunosuppressive functions of MDSCs. We also hope to propose an overview of current MDSCs-targeting therapies so as to provide new ideas for cancer treatment.

Myeloid-Derived Suppressor Cells Dampen Airway Inflammation Through Prostaglandin E2 Receptor 4.

Emerging evidence suggests a mechanistic role for myeloid-derived suppressor cells (MDSCs) in lung diseases like asthma. Previously, we showed that adoptive transfer of MDSCs dampens lung inflammation in murine models of asthma through cyclooxygenase-2 and arginase-1 pathways. Here, we further dissected this mechanism by studying the role and therapeutic relevance of the downstream mediator prostaglandin E2 receptor 4 (EP4) in a murine model of asthma. We adoptively transferred MDSCs generated using an EP4 agonist in a murine model of asthma and studied the consequences on airway inflammation. Furthermore, pegylated human arginase-1 was used to model MDSC effector activities. We demonstrate that the selective EP4 agonist L-902,688 increased the number and suppressive activity of MDSCs through arginase-1 and nitric oxide synthase-2. These results showed that adoptive transfer of EP4-primed MDSCs, EP4 agonism alone or arginase-1 administration ameliorated lung inflammatory responses and histopathological changes in asthmatic mice. Collectively, our results provide evidence that MDSCs dampen airway inflammation in murine asthma through a mechanism involving EP4.

Inhibition of lipid phosphatase SHIP1 expands myeloid-derived suppressor cells and attenuates rheumatoid arthritis in mice.

Rheumatoid arthritis (RA) is a debilitating autoimmune disease of unknown cause, characterized by infiltration and accumulation of activated immune cells in the synovial joints where cartilage and bone destructions occur. Myeloid-derived suppressor cells (MDSCs) are of myeloid origin and are able to suppress T cell responses. Src homology 2 domain-containing inositol polyphosphate 5-phosphatase 1 (SHIP1) was shown to be involved in the regulation of MDSC differentiation. The purpose of the present study was to investigate the effect of inhibition of SHIP1 on the expansion of MDSCs in RA using a collagen-induced inflammatory arthritis (CIA) mouse model. In DBA/1 mice, treatment with a small molecule-specific SHIP1 inhibitor 3α-aminocholestane (3AC) induced a marked expansion of MDSCs in vivo. Both pretreatment with 3AC of DBA/1 mice prior to CIA induction and intervention with 3AC during CIA progression significantly reduced disease incidence and severity. Adoptive transfer of MDSCs isolated from 3AC-treated mice, but not naïve MDSCs from normal mice, into CIA mice significantly reduced disease incidence and severity, indicating that the 3AC-induced MDSCs were the cellular mediators of the observed amelioration of the disease. In conclusion, inhibition of SHIP1 expands MDSCs in vivo and attenuates development of CIA in mice. Small molecule-specific inhibition of SHIP1 may therefore offer therapeutic benefit to patients with RA and other autoimmune diseases.

Analysis of therapeutic potential of monocytic myeloid-derived suppressor cells in cardiac allotransplantation.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) are attractive immune cells to induce immune tolerance. To explore a strategy for improving the efficacy of MDSC therapies, we examined the impact of adoptive transfer of several types of MDSCs on graft rejection in a murine heart transplantation model. METHODS: We analyzed the effects of induced syngeneic and allogeneic bone marrow-derived MDSCs (BM-MDSCs) on graft survival and suppressive capacity. We also compared the ability of syngeneic monocytic MDSCs (Mo-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs) to inhibit graft rejection and investigated the suppression mechanisms. RESULTS: Both syngeneic and allogeneic donor- or allogeneic third-party-derived BM-MDSCs prolonged graft survival, although syngeneic BM-MDSCs inhibited anti-donor immune responses most effectively in vitro. Syngeneic Mo-MDSCs, rather than PMN-MDSCs, were responsible for immune suppression through downregulating inducible nitric oxide synthase (iNOS) and expanded naturally occurring thymic originated Treg (nTreg) in vitro. Adoptive transfer of Mo-MDSCs, but not PMN-MDSCs, prolonged graft survival and increased Treg infiltration into the graft heart. CONCLUSION: Recipient-derived Mo-MDSCs are most effective in prolonging graft survival via inhibiting T cell response and nTreg infiltration.

Dexamethasone and lactoferrin induced PMN-MDSCs relieved inflammatory adverse events of anti-cancer therapy without tumor promotion.

In this era of immune checkpoint inhibitors, inflammatory adverse events of anti-cancer therapies continue to pose a major challenge. Glucocorticoids, as the mainstay, were limited by serious side effects. Glucocorticoids induce myeloid-derived suppressor cells (MDSCs), and lactoferrin-induced polymorphonuclear MDSCs (PMN-MDSCs) were shown to relieve inflammatory conditions. Combined treatment with dexamethasone (DXM) and lactoferrin increased the generation of PMN-MDSCs in vitro (DXM/lactoferrin PMN-MDSCs) compared to DXM or lactoferrin treatment alone. DXM/lactoferrin PMN-MDSCs were distinct from tumor PMN-MDSCs in vivo with regard to gene expression profiles. DXM upregulated the myeloid cell response to lactoferrin by inducing the lactoferrin receptor Lrp1. DXM/lactoferrin PMN-MDSCs presented anti-bacterial capability, increased PGE2 production, increased survival capability, and decreased tumor tissue homing. Transfer of DXM/lactoferrin PMN-MDSCs relieved cisplatin-induced acute kidney failure, bleomycin-induced interstitial pneumonia, and allergic pneumonitis effectively without promoting tumor development. Our study shows that DXM/lactoferrin PMN-MDSCs are a promising cell therapy for inflammatory adverse events of anti-cancer therapies.

Myeloid-derived suppressor cells as cellular immunotherapy in transplantation and autoimmune diseases.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells, which have been characterized for their immunosuppressive capacity through multiple mechanisms. These cells have been extensively studied in the field of tumor immunity. Emerging evidence has highlighted its essential role in maintaining immune tolerance in transplantation and autoimmunity. Because of their robust immune inhibitory activities, there has been growing interest in MDSC-based cellular therapy. Various pre-clinical studies have demonstrated that the adoptive transfer of MDCS represented a promising therapeutic strategy for immune-related disorders. In this review, we summarize relevant studies of MDSC-based cell therapy in transplantation and autoimmune diseases and discuss the challenges and future directions for clinical application of MDSC-based cell therapy.

CHBP induces stronger immunosuppressive CD127+ M-MDSC via erythropoietin receptor.

Erythropoietin (EPO) is not only an erythropoiesis hormone but also an immune-regulatory cytokine. The receptors of EPO (EPOR)2 and tissue-protective receptor (TPR), mediate EPO's immune regulation. Our group firstly reported a non-erythropoietic peptide derivant of EPO, cyclic helix B peptide (CHBP), which could inhibit macrophages inflammation and dendritic cells (DCs) maturation. As a kind of innate immune regulatory cell, myeloid-derived suppressor cells (MDSCs) share a common myeloid progenitor with macrophages and DCs. In this study, we investigated the effects on MDSCs differentiation and immunosuppressive function via CHBP induction. CHBP promoted MDSCs differentiate toward M-MDSCs with enhanced immunosuppressive capability. Infusion of CHBP-induced M-MDSCs significantly prolonged murine skin allograft survival compared to its counterpart without CHBP stimulation. In addition, we found CHBP increased the proportion of CD11b+Ly6G-Ly6Chigh CD127+ M-MDSCs, which exerted a stronger immunosuppressive function compared to CD11b+Ly6G-Ly6Chigh CD127- M-MDSCs. In CHBP induced M-MDSCs, we found that EPOR downstream signal proteins Jak2 and STAT3 were upregulated, which had a strong relationship with MDSC function. In addition, CHBP upregulated GATA-binding protein 3 (GATA-3) protein translation level, which was an upstream signal of CD127 and regulator of STAT3. These effects of CHBP could be reversed if Epor was deficient. Our novel findings identified a new subset of M-MDSCs with better immunosuppressive capability, which was induced by the EPOR-mediated Jak2/GATA3/STAT3 pathway. These results are beneficial for CHBP clinical translation and MDSC cell therapy in the future.

Therapeutic Role of Inducible Nitric Oxide Synthase Expressing Myeloid-Derived Suppressor Cells in Acetaminophen-Induced Murine Liver Failure.

Background: Acetaminophen (APAP) overdose is one of the major etiologies of liver failure. Hepatocyte necrosis induced by toxic metabolites of APAP can activate proinflammatory responses, including elastase-expressing neutrophils, to exacerbate liver injury. Myeloid-derived suppressor cells (MDSCs) increased in inflammation can inhibit proinflammatory responses. Our aim is to investigate the role of MDSC in APAP-induced liver failure and the possible therapeutic application. Methods: BLAB/c mice were injected with a sublethal/lethal dose of APAP as the murine model of liver failure. MDSCs were defined as CD11b+Gr-1+ cells with the ability of T-cell suppression. Results: A sublethal challenge of APAP could increase the intrahepatic MDSC and protect mice against subsequent lethal challenge of APAP, lipopolysaccharide (LPS)/D-galatosamine or concanavalin A. This protection was lost if MDSCs were depleted and inducible nitric oxide synthase (iNOS) was the key molecule in this MDSC-mediated protection. Taking advantage of these observations, different bone marrow-derived MDSCs (BM-MDSCs) were generated. Among different cytokine-treated BM-MDSCs, tumor necrosis factor alpha/LPS-primed MDSCs (TNF-α/LPS MDSCs) had the strongest liver-protection ability after adoptive transfer. Further mechanistic explorations showed, iNOS-expressing TNF-α/LPS MDSCs induced the apoptosis of activated neutrophil and decreased the intrahepatic infiltration of elastase-expressing neutrophil. Moreover, we generated MDSCs from human peripheral blood mononuclear cells (PBMCs) with similar phenotype. Conclusion: We demonstrated the protective role of MDSCs and therapeutic effect of TNF-α/LPS MDSCs in APAP-induced liver failure. MDSC might protect against the APAP-induced liver failure by reducing the intrahepatic infiltration of activated neutrophil to limit inflammation. Therefore, a therapeutic role of MDSCs for APAP-induced liver failure was proposed.

Can we prevent or treat graft-versus-host disease with cellular-therapy?

Acute and chronic graft-versus-host disease (GvHD) are the most important causes of treatment-related morbidity and mortality after allogeneic hematopoietic cell transplants for various diseases. Corticosteroids are an effective therapy in only about one-half of affected individuals and new therapy options are needed. We discuss novel strategies to treat GvHD using cellular-therapy including adoptive transfer of regulatory T-cells (Tregs), mesenchymal stromal cells (MSCs), cells derived from placental tissues, invariant natural killer T-cells (iNKTs), and myeloid-derived suppressor cells (MDSCs).These strategies may be more selective than drugs in modulating GvHD pathophysiology, and may be safer and more effective than conventional pharmacologic therapies. Additionally, these therapies have not been observed to substantially compromise the graft-versus-tumor effect associated with allotransplants. Many of these strategies are effective in animal models but substantial data in humans are lacking.

Donor-Derived Myeloid Heme Oxygenase-1 Controls the Development of Graft-Versus-Host Disease.

Graft-versus-host disease (GVHD) remains a major clinical drawback of allogeneic hematopoietic stem cell transplantation (HSCT). Here, we investigated how the stress responsive heme catabolizing enzyme heme oxygenase-1 (HO-1, encoded by HMOX1) regulates GVHD in response to allogeneic hematopoietic stem cell transplantation in mice and humans. We found that deletion of the Hmox1 allele, specifically in the myeloid compartment of mouse donor bone marrow, promotes the development of aggressive GVHD after allogeneic transplantation. The mechanism driving GVHD in mice transplanted with allogeneic bone marrow lacking HO-1 expression in the myeloid compartment involves enhanced T cell alloreactivity. The clinical relevance of these observations was validated in two independent cohorts of HSCT patients. Individuals transplanted with hematopoietic stem cells from donors carrying a long homozygous (GT)n repeat polymorphism (L/L) in the HMOX1 promoter, which is associated with lower HO-1 expression, were at higher risk of developing severe acute GVHD as compared to donors carrying a short (GT)n repeat (S/L or S/S) polymorphism associated with higher HO-1 expression. In this study, we showed the unique importance of donor-derived myeloid HO-1 in the prevention of lethal experimental GVHD and we corroborated this observation by demonstrating the association between human HMOX1 (GT)n microsatellite polymorphisms and the incidence of severe acute GVHD in two independent HSCT patient cohorts. Donor-derived myeloid HO-1 constitutes a potential therapeutic target for HSCT patients and large-scale prospective studies in HSCT patients are necessary to validate the HO-1 L/L genotype as an independent risk factor for developing severe acute GVHD.

Emerging Role of Myeloid-derived Suppressor Cells in the Biology of Transplantation Tolerance.

Myeloid-derived suppressor cells (MDSCs), a heterogeneous population of myeloid cells, are characterized by their immunosuppressive abilities through the secretion of various cytokines such as inducible nitric oxide synthase, nitric oxide, reactive oxygen species, transforming growth factor-ß, and arginase-1. Accumulating evidence highlights its potential role in maintaining immune tolerance in solid organ and hematopoietic stem cell transplantation. Mechanistically, MDSCs-induced transplant tolerance is mainly dependent on direct suppression of allogeneic reaction or strengthened cross-talk between MDSCs and Treg or NKT cells. Adopted transfer of in vitro- or in vivo-induced MDSCs by special drugs therefore becomes a potential strategy for maintaining transplantation tolerance. In this review, we will summarize the previously published data about the role of MDSCs in the biology of transplantation tolerance and gain insights into the possible molecular mechanism governing this process.

A Strategy for Suppressing Macrophage-mediated Rejection in Xenotransplantation.

Although xenografts are one of the most attractive strategies for overcoming the shortage of organ donors, cellular rejection by macrophages is a substantial impediment to this procedure. It is well known that macrophages mediate robust immune responses in xenografts. Macrophages also express various inhibitory receptors that regulate their immunological function. Recent studies have shown that the overexpression of inhibitory ligands on porcine target cells results in the phosphorylation of tyrosine residues on intracellular immunoreceptor tyrosine-based inhibitory motifs on macrophages, leading to the suppression of xenogenic rejection by macrophages. It has also been reported that myeloid-derived suppressor cells, a heterogeneous population of immature myeloid cells, suppress not only NK and cytotoxic T lymphocyte cytotoxicity but also macrophage-mediated cytotoxicity. This review is focused on the recent findings regarding strategies for inhibiting xenogenic rejection by macrophages.

Danger-associated extracellular ATP counters MDSC therapeutic efficacy in acute GVHD.

Myeloid-derived suppressor cells (MDSCs) can subdue inflammation. In mice with acute graft-versus-host disease (GVHD), donor MDSC infusion enhances survival that is only partial and transient because of MDSC inflammasome activation early posttransfer, resulting in differentiation and loss of suppressor function. Here we demonstrate that conditioning regimen-induced adenosine triphosphate (ATP) release is a primary driver of MDSC dysfunction through ATP receptor (P2x7R) engagement and NLR pyrin family domain 3 (NLRP3) inflammasome activation. P2x7R or NLRP3 knockout (KO) donor MDSCs provided significantly higher survival than wild-type (WT) MDSCs. Although in vivo pharmacologic targeting of NLRP3 or P2x7R promoted recipient survival, indicating in vivo biologic effects, no synergistic survival advantage was seen when combined with MDSCs. Because activated inflammasomes release mature interleukin-1ß (IL-1ß), we expected that IL-1ß KO donor MDSCs would be superior in subverting GVHD, but such MDSCs proved inferior relative to WT. IL-1ß release and IL-1 receptor expression was required for optimal MDSC function, and exogenous IL-1ß added to suppression assays that included MDSCs increased suppressor potency. These data indicate that prolonged systemic NLRP3 inflammasome inhibition and decreased IL-1ß could diminish survival in GVHD. However, loss of inflammasome activation and IL-1ß release restricted to MDSCs rather than systemic inhibition allowed non-MDSC IL-1ß signaling, improving survival. Extracellular ATP catalysis with peritransplant apyrase administered into the peritoneum, the ATP release site, synergized with WT MDSCs, as did regulatory T-cell infusion, which we showed reduced but did not eliminate MDSC inflammasome activation, as assessed with a novel inflammasome reporter strain. These findings will inform future clinical using MDSCs to decrease alloresponses in inflammatory environments.

Lactoferrin-induced myeloid-derived suppressor cell therapy attenuates pathologic inflammatory conditions in newborn mice.

Inflammation plays a critical role in the development of severe neonatal morbidities. Myeloid-derived suppressor cells (MDSCs) were recently implicated in the regulation of immune responses in newborns. Here, we report that the presence of MDSCs and their functional activity in infants are closely associated with the maturity of newborns and the presence of lactoferrin (LF) in serum. Low amounts of MDSCs at birth predicted the development of severe pathology in preterm infants - necrotizing enterocolitis (NEC). In vitro treatment of newborn neutrophils and monocytes with LF converted these cells to MDSCs via the LRP2 receptor and activation of the NF-κB transcription factor. Decrease in the expression of LRP2 was responsible for the loss of sensitivity of adult myeloid cells to LF. LF-induced MDSCs (LF-MDSCs) were effective in the treatment of newborn mice with NEC, acting by blocking inflammation, resulting in increased survival. LF-MDSCs were more effective than treatment with LF protein alone. In addition to affecting NEC, LF-MDSCs demonstrated potent ability to control ovalbumin-induced (OVA-induced) lung inflammation, dextran sulfate sodium-induced (DSS-induced) colitis, and concanavalin A-induced (ConA-induced) hepatitis. These results suggest that cell therapy with LF-MDSCs may provide potent therapeutic benefits in infants with various pathological conditions associated with dysregulated inflammation.

Preliminary assessment of the feasibility of autologous myeloid-derived suppressor cell infusion in non-human primate kidney transplantation.

Myeloid-derived suppressor cells (MDSC) are a heterogenous population of immunosuppressive myeloid cells now considered important immune regulatory cells in diverse clinical conditions, including cancer, chronic inflammatory disorders and transplantation. In rodents, MDSC administration can inhibit graft-versus-host disease lethality and enhance organ or pancreatic islet allograft survival. There is also evidence, however, that under systemic inflammatory conditions, adoptively-transferred MDSC can rapidly lose their suppressive function. To our knowledge, there are no reports of autologous MDSC administration to either human or clinically-relevant non-human primate (NHP) transplant recipients. Monocytic (m) MDSC have been shown to be more potent suppressors of T cell responses than other subsets of MDSC. Following their characterization in rhesus macaques, we have conducted a preliminary analysis of the feasibility and preliminary efficacy of purified mMDSC infusion into MHC-mismatched rhesus kidney allograft recipients. The graft recipients were treated with rapamycin and the high affinity variant of the T cell co-stimulation blocking agent cytotoxic T lymphocyte antigen 4 Ig (Belatacept) that targets the B7-CD28 pathway. Graft survival and histology were not affected by infusions of autologous, leukapheresis product-derived mMDSC on days 7 and 14 post-transplant (cumulative totals of 3.19 and 1.98 × 106 cells/kg in n = 2 recipients) compared with control monkeys that did not receive MDSC (n = 2). Sequential analyses of effector T cell populations revealed no differences between the groups. While these initial findings do not provide evidence of efficacy under the conditions adopted, further studies in NHP, designed to ascertain the appropriate mMDSC source and dose, timing and anti-inflammatory/immunosuppressive agent support are likely to prove instructive regarding the therapeutic potential of MDSC in organ transplantation.

Correlation between MDSC and Immune Tolerance in Transplantation: Cytokines, Pathways and Cell-cell Interaction.

MDSCs play an important role in the induction of immune tolerance. Cytokines and chemokines (GM-CSF, IL-6) contributed to the expansion, accumulation of MDSCs, and MDSCs function through iNOS, arginase and PD-L1. MDSCs are recruited and regulated through JAK/STAT, mTOR and Raf/MEK/ERK signaling pathways. MDSCs' immunosuppressive functions were realized through Tregs-mediated pathways and their direct suppression of immune cells. All of the above contribute to the MDSC-related immune tolerance in transplantation. MDSCs have huge potential in prolonging graft survival and reducing rejection through different ways and many other factors worthy to be further investigated are also introduced.

α-Difluoromethylornithine suppresses inflammatory arthritis by impairing myeloid-derived suppressor cells.

OBJECTIVES: The chemopreventive drug α-difluoromethylornithine (DFMO) has been shown to have an antinociceptive effect on mechanical allodynia in inflammatory arthritis by directly inhibiting ornithine decarboxylase (ODC) and decreasing polyamine production in inflammatory sites. However, little is known about the effect of DFMO on the immune system of inflammatory arthritis. Here, we investigated the effect of DFMO in a well-established collagen-induced arthritis (CIA) mouse model and explored its effect on the immune system. METHODS: The effect of DFMO on the frequency of myeloid-derived suppressor cells (MDSCs) in the spleens of CIA mice and their associations with disease severity, tissue inflammation and the levels of proinflammatory T-helper (Th) 17 cells in lymphoid tissues were investigated. The effects of DFMO on disease severity and Th17 cells were compared with those of antibody depletion of MDSCs. The arthritis severity was also evaluated by adoptive transfer of MDSCs derived from DFMO- or dH2O-treated mice. RESULTS: In this study, we showed that both MDSCs and Th17 cells were significantly expanded in CIA mice. Treatment by DFMO at the onset of CIA suppressed the development of arthritis and decreased the frequency of MDSCs and Th17 cells. MDSC depletion by anti-Gr-1 mAb achieved a similar result, while combination treatment of both methods did not achieve a significant difference compared to either of the single treatments. In addition, the adoptive transfer of MDSCs derived from dH2O-treated mice with CIA restored the arthritis severity of CIA in mice treated with anti-Gr-1 mAb, while the transfer of MDSCs from DFMO-treated mice did not have such an effect. CONCLUSIONS: Our results identified DFMO as a potential therapeutic drug for the treatment of inflammatory arthritis.

Glucocorticoids induce corneal allograft tolerance through expansion of monocytic myeloid-derived suppressor cells.

Glucocorticoids (GCs) are the most widely used drugs to prevent transplant rejection; however, it is not yet clear how GCs induce immune tolerance in transplantation. Here, we demonstrate that GCs induce tolerance to corneal allografts in mice through expansion of MHC class II- CD11b+ Ly6C+ monocytes in the bone marrow and mobilization of the cells to spleen, draining lymph nodes, and graft site. The GC-induced CD11b+ Ly6C+ monocytes inhibited T cell proliferation in vitro, and adoptive transfer of the cells improved the survival of corneal allografts. Depletion of CD11b+ Ly6C+ cells in mice during GC treatment abrogated the effects of GCs in prevention of immune rejection. Together, the results identify monocytic myeloid-derived suppressor cells as crucial mediators of the GC-induced tolerance in transplantation.

The Highly Metastatic Nature of Uterine Cervical/Endometrial Cancer Displaying Tumor-Related Leukocytosis: Clinical and Preclinical Investigations.

Purpose: The aim of this study was to investigate the metastatic potential of uterine cervical and endometrial cancer displaying tumor-related leukocytosis (TRL).Experimental Design: Clinical data on uterine cervical (N = 732) and endometrial cancer (N = 900) were collected, and the metastatic potential of TRL-positive cancer was evaluated in univariate and multivariate analyses. Tumor and blood samples obtained from patients with cervical cancer, cervical cancer cell lines, and a mouse model of cervical cancer were used to examine the mechanisms underlying the highly metastatic nature of TRL-positive cancer, focusing on tumor-derived G-CSF and the myeloid-derived suppressor cell (MDSC)-mediated premetastatic niche.Results: Pretreatment TRL was significantly associated with visceral organ metastasis in patients with uterine cervical or endometrial cancer. The patients with TRL-positive cervical cancer displayed upregulated tumor G-CSF expression, elevated G-CSF levels, and increased MDSC frequencies in the peripheral blood compared with the TRL-negative patients. In vitro and in vivo investigations revealed that MDSCs produced in response to tumor-derived G-CSF are involved in premetastatic niche formation, which promotes visceral organ metastasis of TRL-positive cancer. The depletion of MDSCs attenuated this premetastatic niche formation and effectively inhibited the visceral organ metastasis of TRL-positive cancer.Conclusions: Uterine cervical/endometrial cancer displaying TRL is a distinct clinical entity with high metastatic potential. Tumor-derived G-CSF and the MDSC-mediated premetastatic niche are responsible for the highly metastatic nature of this type of cancer. MDSC-targeting therapy might represent a potential strategy for combating metastasis derived from TRL-positive uterine cancer. Clin Cancer Res; 24(16); 4018-29. ©2018 AACR.