PGE2-Driven Induction and Maintenance of Cancer-Associated Myeloid-Derived Suppressor Cells

Myeloid-derived suppressor cells (MDSCs) are critical mediators of tumor-associated immune suppression, with their numbers and activity strongly increased in most human cancers and animal models. MDSCs suppress anti-tumor immunity through multiple mechanisms, including the manipulation of arginine and tryptophan metabolism by such factors as arginase (Arg), inducible nitric oxide synthase (iNOS/NOS2), and indoleamine-2,3-dioxygenase (IDO). Prostaglandin E₂ (PGE₂), a mediator of chronic inflammation and tumor progression, has emerged as a key molecule in MDSC biology. PGE₂ promotes MDSC development and their induction by additional factors, directly suppresses T cell immune responses and participates in the induction of other MDSC-associated suppressive factors, including Arg, iNOS and IDO. It further promotes MDSC recruitment to tumor environments through the local induction of CXCL12/SDF-1 and the induction and stabilization of the CXCL12 receptor, CXCR4, on tumor-associated MDSCs. The establishment of a positive feedback loop between PGE₂ and cyclooxygenase 2 (COX-2), the key regulator of PGE₂ synthesis, stabilizes the MDSC phenotype and is required for their suppressive function. The central role of PGE₂ in MDSC biology provides for a feasible target for counteracting MDSC-mediated immune suppression in cancer.     

Splenectomy-Induced Leukocytosis Promotes Intratumoral Accumulation of Myeloid-Derived Suppressor Cells,Angiogenesis and Metastasis

Background: Enlargement of the spleen is commonly observed in animal models of cancer. Here, in a breast cancer model, it was aimed to determine the effect of splenectomy on circulating and tumor-infiltrating myeloid-derived suppressor cells (MDSCs), tumor angiogenesis, and metastasis.

Methods: Mice were inoculated with 4T1 breast cancer cells and underwent splenectomy or sham laparotomy. Tumor growth and survival of animals were followed. Macroscopic and histopathological analyses were performed to determine splenomegaly and metastasis. Immunophenotyping of myeloid cells was performed with flow cytometric analysis of CD11b, Gr-1, F4/80, CD206, CD11c, and F4/80 markers. Suppressive function of MDSCs on T cell proliferation was studied in cocultures. Tumor angiogenesis and granulocytic myeloid cell infiltration in the metastatic foci were studied by CD31 and Ly6G immunohistochemistry, respectively.

Results: The mice bearing breast tumors underwent total splenectomy at an early time point of tumorigenesis when only low levels of MDSCs had accumulated in the spleen. Circulating and tumor-infiltrating MDSCs, and tumor-associated macrophages (TAMs) were increased following splenectomy. Nevertheless, splenectomy could only lead to a temporary deceleration in tumor growth but favored lung metastasis and angiogenesis in the long run.

Conclusion: Our data demonstrated a link among splenectomy-induced leukocytosis, accumulation of circulating and tumor-infiltrating MDSC, and enhanced angiogenesis and metastasis. Therefore, as a part of oncological surgery, favorable and unfavorable facets of the splenectomy must be considered to improve therapeutic efficacy.     

Clinical Significance and Functional Studies of Myeloid-Derived Suppressor Cells in Chronic Hepatitis C Patients

Purpose

Myeloid-derived suppressor cells (MDSCs) are known to accumulate under some pathologic conditions and suppress immune system in a variety of ways. This study aims to evaluate the significance of MDSCs in chronic Hepatitis C (CHC) patients.

Methods

14 CHC patients and healthy donors were enrolled and subject to antiviral therapy including Peg-INF-alpha and Ribavirin for 48 weeks. The peripheral blood mononuclear cells (PBMCs) were collected at different weeks post-therapy and MDSC frequency was analyzed by flow cytometry. The correlation between MDSCs level with CHC disease parameters was analyzed by Spearman’s rank test. The suppressive function of MDSCs from CHC patients and the underlying mechanism was further evaluated.

Results

A significant elevation of MDSCs was observed in the peripheral blood of treatment-naive CHC patients compared with healthy donors. The level of MDSCs in CHC patients correlated with plasma HCV-RNA (r?=?0.7164, p?=?0.0039), blood aminotransaminase (r?=?0.6116, p?=?0.021), and activated CD38⁺ T cells (CD4⁺: r?=?0.6649, p?=?0.0095; CD8⁺: r?=?0.6189, p?=?0.0189). Initiation of clinical therapy reduced MDSC levels as early as 4 weeks, while it rebounded at week 12 post-therapy in patients. CHC-derived MDSCs could suppress T cell function in an arginase-1-dependent manner, that was distinct from the HCV core protein-generated MDSCs as previously reported.

Conclusion

Our study reveals a significant correlation between MDSC levels with HCV disease progression, and their response to antiviral therapy. The arginase-1-dependent mechanism of MDSCs from CHC patients indicates that arginase-1 may be promising target for HCV immunotherapy.     

Dynamic Change and Impact of Myeloid-Derived Suppressor Cells in Allogeneic Bone Marrow Transplantation in Mice

Myeloid-derived suppressor cells (MDSCs) are a group of myeloid cells composed of hematopoietic progenitor cells, immature macrophages, dendritic cells, and granulocytes, which accumulate in inflammatory diseases and various cancers. Here, we investigated the dynamic changes and effects of MDSCs in graft-versus-host disease (GVHD) development and/or tumor relapse after syngeneic and allogeneic bone marrow transplantation (BMT). We found that adding functional MDSCs in donor graft alleviated GVHD, whereas removal of MDSCs in vivo exacerbated GVHD. After T cell-deplete BMT, MDSCs transiently accumulated in the blood and spleen of recipients without GVHD. In contrast, after T cell-replete BMT, the levels of blood MDSCs were constantly elevated in recipients with GVHD. MDSC accumulation positively correlated with the severity of GVHD. Additionally, MDSC accumulation was further increased upon tumor relapse. Although MDSCs isolated from both syngeneic and allogeneic BMT recipients inhibited T cell proliferation in response to alloantigen stimulation ex vivo, MDSCs from the recipients with GVHD showed much higher suppressive potency compared with those from recipients without GVHD. These results indicate that MDSCs can regulate the immune response in acute GVHD, and possibly tumor relapse, subsequent to allogeneic BMT.     

Clinical Significance of Myeloid-Derived Suppressor Cells in Human Renal Transplantation with Acute T Cell-Mediated Rejection

Myeloid-derived suppressor cells (MDSCs) are negative regulators of the immune response and are in part responsible for the inhibition of the T cell-mediated immune response. A recent paper indicated that MDSCs were involved in prolonged allograft survival in animal models of transplantation, but the significance of MDSCs in human renal transplantation is still unknown. In our study, 50 patients with biopsy-proven acute T cell-mediated rejection (ATCMR) were included. The ratio of MDSCs in peripheral blood mononuclear cell (PBMC) was evaluated with FACS, and the patients were divided into the MDSCs high group (MDSCs, >10 %) or the MDSCs low group (MDSCs, <10 %). We compared the allograft function, severity of tissue injury, and long-time survival between the two groups. In the MDSCs high group, allograft function was significantly increased compared with the MDSCs low group. Furthermore, we found that isolated MDSCs from transplant recipients are capable of expanding regulatory T cell (Treg), meanwhile, inhibiting production of IL-17 in vitro. We also found that the ratio between Foxp3⁺ and IL-17-producing CD4⁺ T cells positively correlated with MDSCs frequency in PBMC. In conclusion, we demonstrated a potential role for MDSCs in prolonging allograft survival after ATCMR, and this was associated with higher CD4⁺Foxp3⁺/CD4⁺IL-17⁺ ratio in PBMC.     

Myeloid-Derived Suppressor Cells in the Tumor Microenvironment: Current Knowledge and Future Perspectives

Archivum Immunologiae et Therapiae Experimentalis - The current knowledge on tumor-infiltrating myeloid-derived suppressor cells (MDSCs) is based mainly on the extensive work performed in murine...     

Dysregulated Immunometabolism Is Associated with the Generation of Myeloid-Derived Suppressor Cells in Staphylococcus aureus Chronic Infection

Myeloid-derived suppressor cells (MDSCs) are a compendium of immature myeloid cells that exhibit potent T-cell suppressive capacity and expand during pathological conditions such as cancer and chronic infections. Although well-characterized in cancer, the physiology of MDSCs in the infection setting remains enigmatic. Here, we integrated single-cell RNA sequencing (scRNA-seq) and functional metabolic profiling to gain deeper insights into the factors governing the generation and maintenance of MDSCs in chronic Staphylococcus aureus infection. We found that MDSCs originate not only in the bone marrow but also at extramedullary sites in S. aureus-infected mice. scRNA-seq showed that infection-driven MDSCs encompass a spectrum of myeloid precursors in different stages of differentiation, ranging from promyelocytes to mature neutrophils. Furthermore, the scRNA-seq analysis has also uncovered valuable phenotypic markers to distinguish mature myeloid cells from immature MDSCs. Metabolic profiling indicates that MDSCs exhibit high glycolytic activity and high glucose consumption rates, which are required for undergoing terminal maturation. However, rapid glucose consumption by MDSCs added to infection-induced perturbations in the glucose supplies in infected mice hinders the terminal maturation of MDSCs and promotes their accumulation in an immature stage. In a proof-of-concept in vivo experiment, we demonstrate the beneficial effect of increasing glucose availability in promoting MDSC terminal differentiation in infected mice. Our results provide valuable information of how metabolic alterations induced by infection influence reprogramming and differentiation of MDSCs.     

High Frequency of Mononuclear Myeloid-Derived Suppressor Cells is Associated with Exacerbation of Inflammatory Bowel Disease

Exacerbation and relapse of inflammatory bowel disease (IBD) is associated with reduced antibacterial immunity and increased immune regulatory activity, but the source of increased immune regulation during episodes of disease activity is unclear. Myeloid-derived suppressor cells (MDSCs) are a cell type with a well-recognized role in limiting immune reactions. MDSC function in IBD and its relation to disease activity, however, remains unexplored. Here we show that patients with either ulcerative colitis (UC) or Crohn's disease (CD) have high peripheral blood levels of mononuclear MDSCs. Especially exacerbation of disease is associated with higher levels of mononuclear MDSC counts compared with those in remission of disease. Interestingly, chronic experimental colitis in mice coincides with increased MDCS mobilization. Thus, our results suggest that mononuclear MDCS are endogenous antagonists of immune system functionality in mucosal inflammation and the depression of antibacterial immunity associated with exacerbation of disease might involve increased activity of the MDSC compartment.     

Placental Products Induce Suppressor Cells of Graft Versus Host Reaction

ABSTRACT: Cells from mice alloimmunized in the presence of placental extract were coinjected with cells from mice conventionally alloimmunized in the footpad of virgin female recipients. The contralateral footpad received a control twice the dose of cells from alloimmunized mice. Cells from the popliteal lymph nodes were harvested on day 3, and pulsed in vitro for measurement of proliferative capacity with ³H thymidine. The response of lymph nodes was compared (homo- vs contralateral). The cells from mice alloimmunized with placental extract in conjunction with alloantigens displayed a marked suppressive capacity of the local graft versus host (GVH) potential of cells from mice conventionally alloimmunized. It is suggested that this local GVH assay represents a quick, objective assay for suppressor-cell induction by placental products.     

Bendamustine with Total Body Irradiation Limits Murine Graft-versus-Host Disease in Part Through Effects on Myeloid-Derived Suppressor Cells

Graft-versus-host disease (GVHD) remains a significant challenge in allogeneic hematopoietic cell transplantation (HCT). An underinvestigated strategy to reduce GVHD is the modification of the preparative conditioning regimen. In the present study, we aimed to evaluate GVHD associated with bendamustine (BEN) conditioning in conjunction with total body irradiation (TBI) as an alternative to the standard myeloablative regimen of cyclophosphamide (CY) and TBI. We demonstrate that BEN-TBI conditioning, although facilitating complete donor chimerism, results in significantly less GVHD compared with CY-TBI. In BEN-TBI-conditioned mice, suppressive CD11b⁺Gr-1^high myeloid cells are increased in the blood, bone marrow, spleen, and intestines. When Gr-1^high cells are depleted before transplantation, the beneficial effects of BEN-TBI are partially lost. Alternatively, administration of granulocyte colony-stimulating factor, which promotes CD11b⁺Gr-1⁺ myeloid cell expansion, is associated with a trend toward increased survival in BEN-TBI-conditioned mice. These findings indicate a potential role of myeloid-derived suppressor cells in the mechanism by which BEN allows engraftment with reduced GVHD. BEN-TBI conditioning may present a safer alternative to CY-TBI conditioning for allogeneic HCT.     

Metabolism of L-Arginine by Myeloid-Derived Suppressor Cells in Cancer: Mechanisms of T cell suppression and Therapeutic Perspectives

Patients with cancer have an impaired T cell response that can decrease the potential therapeutic benefit of cancer vaccines and other forms of immunotherapy. The establishment of a chronic inflammatory environment in patients with cancer plays a critical role in the induction of T cell dysfunction. The accumulation of myeloid-derived suppressor cells (MDSC) in tumor bearing hosts is a hallmark of malignancy-associated inflammation and a major mediator of the induction of T cell suppression in cancer. Recent findings in tumor bearing mice and cancer patients indicate that the increased metabolism of L-Arginine (L-Arg) by MDSC producing Arginase I inhibits T cell lymphocyte responses. Here, we discuss some of the most recent concepts of how MDSC expressing Arginase I may regulate T cell function in cancer and suggest possible therapeutic interventions to overcome this inhibitory effect.     

宫颈癌组织内骨髓来源抑制性细胞频率与患者预后的关系

目的 研究宫颈癌患者癌组织与非癌组织中骨髓来源抑制性细胞(MDSCs)和调节性T细胞(Tregs)的频率及功能.方法 收集宫颈癌患者的宫颈组织标本,分为癌组织和非癌组织两组,使用胰酶消化法处理成单细胞悬液,使用流式细胞仪分析两组之间MDSCs和Treg细胞的频率和功能的差异.结果 宫颈癌患者癌组织中单核细胞型(Mo)-...