Characterization of Multiple Cytokine Combinations and TGF-β on Differentiation and Functions of Myeloid-Derived Suppressor Cells

Lee, Cho-Rong; Lee, Wongeun; Cho, Steve K.; Park, Sung‐Gyoo

doi:10.3390/ijms19030869

Cited by 67 publications

(49 citation statements)

References 29 publications

(48 reference statements)

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“…Lee et al have found Treg-derived TGF-β could e ciently promote MDSC proliferation and function in murine colitis (47). A recent study also reported that TGF-β could increase the expansion of MDSCs and enhance the suppressive capacity of MDSCs in vitro (48). Similarly, in our experiment, the canonical signaling of TGF-β was activated, the phosphorylation of Smad2 and Smad3 was strikingly enhanced in MDSCs cocultured with BM-MSCs.…”

Section: Discussionsupporting

confidence: 78%

Mesenchymal stem cell enhances the function of MDSCs in experimental Sjögren syndrome mice

Tian

Hong

Zhu

et al. 2020

Preprint

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Background Primary Sjögren’s syndrome (pSS) is a chronic systemic autoimmune disease characterized by lymphocytic infiltrates in exocrine glands. Mesenchymal stem cells (MSCs) have been proved to be effective in the treatment of different autoimmune diseases. Although MSC transplantation has been demonstrated to be an effective therapeutic approach to treat SS, the underlying mechanisms are still elusive. Our previous study has identified the reduced suppressive capacity of MDSCs advanced the progression of experimental Sjögren’s syndrome (ESS). Methods The ESS mouse model was induced with murine salivary glands proteins emulsified in an equal volume of Freund’s adjuvant. Both frequency and phenotype of MDSCs during ESS development in mice were analyzed by flow cytometry. The suppressive capacity of MDSCs was examined by CD4+ T cell proliferation test, CFSE-labelled CD4+ T cell was analyzed by flow cytometry. Both phenotype and function of MDSCs upon MSCs treatment were analyzed in vitro and in vivo. The function of MSCs in modulating the suppressive function of MDSCs was further evaluated by silencing TGF-β in MSCs. Results In this study, we found that BM-MSCs significantly enhanced the suppressive function of MDSCs (PMN-MDSCs/M-MDSCs) with high levels of Arginase and NO, decreased the levels of CD40, CD80, CD86 and MHC-II expression on MDSCs, thus attenuating the disease progression in ESS mice. Furthermore, the enhanced suppressive function of MDSCs was mediated by BM-MSC-secreted TGF-β, and the therapeutic effect of BM-MSCs in inhibiting ESS was almost abolished after silencing TGF-β in BM-MSCs. Conclusions Taken together, our results demonstrated that BM-MSCs alleviated the ESS progression by up-regulating the immunosuppressive effect of MDSCs through TGF-β/Smad pathway, offering a novel mechanism for MSCs in the treatment of pSS.

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Section: Discussionsupporting

confidence: 78%

Mesenchymal stem cell enhances the function of MDSCs in experimental Sjögren syndrome mice

Tian

Hong

Zhu

et al. 2020

Preprint

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“…Still little is known about the mechanisms that lead to the increasing of M-MDSC, especially in the microenvironment of leukemia [20] and lymphoma [24]. Lee et al [36] found that TGF-b induced the expansion of the monocytic MDSC population, expression of immunosuppressive molecules by MDSCs, and the ability of MDSCs to suppress CD4+ T cell proliferation. In our study, we found a significantly higher percentage of M-MDSC with intracellular IL-10 or TGF-b expression in CLL patients than in healthy volunteers.…”

Section: Discussionmentioning

confidence: 99%

Monocytic MDSC as a source of immunosuppressive cytokines in chronic lymphocytic leukemia (CLL) microenvironment

Kowalska

2020

Folia Histochem Cytobiol.

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Introduction. Myeloid derived suppressor cells (MDSCs) are one of the major components of the tumor microenvironment. The accumulation of MDSCs has been demonstrated in many types of human solid tumors. However, the relevance of this heterogeneous population in hematopoietic malignancies has only recently gained stronger attention. MDSCs are a phenotypically and functionally heterogeneous group of cells. The results of recent studies indicate that the immune dysregulation in chronic lymphocytic leukemia (CLL) affects a monocytic MDSC (M-MDSC) subpopulation. This study aimed to analyze the frequency of M-MDSCs with intracellular IL-10 and TGF-b1 expression in newly diagnosed CLL patients. We investigated the potential role of M-MDSCs in CLL by analyzing the level of IL-10 and TGF-b1 expression in circulating M-MDSCs in correlation with clinical and laboratory parameters characterizing disease activity and patients' immune status. Material and methods. Seventy CLL patients and 17 age-matched healthy volunteers were included in this study. Flow cytometric detection of Mo-MDSCs (CD14 + CD11b + CD15-HLA-DR-/low) with intracellular IL-10 and TGF-b1 expression was done. Results. We found a significantly higher median percentage of M-MDSC with IL-10 or TGF-b1 expression in CLL patients than in healthy volunteers. The percentage of M-MDSC with intracellular IL-10 or TGF-b1 expression was significantly lower in CLL patients at stage 0 as compared to the stages I/II and III/IV according to Rai stages. The percentage of M-MDSC with intracellular TGF-b1 expression was significantly higher in ZAP-70-positive and CD38-positive patients compared with ZAP-70-negative and group of CD38-negative ones. There was also a significantly higher percentage of M-MDSC positive for intracellular TGF-b expression in patients carrying the 11q22.3 and/or the 17p13.1 deletion than in patients without these genetic aberrations. The percentage of M-MDSC IL-10-positive and M-MDSC TGF-b1-positive measured at the time of diagnosis was higher in patients requiring therapy as compared to patients without treatment during the observation period. Conclusion. In conclusion, we have shown that an increased percentage of M-MDSC cells producing IL-10 and TGF-b1 in CLL patients may be associated with the suppression of the immune response against CLL. It can be assumed that the increased percentage of M-MDSC with an intracellular expression of IL-10 and TGF-b1 may be used in the future as the factor defining the group of patients with shorter time to onset of treatment.

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“…We also presume that myelosuppression occurring in severe neutropenic patients contributes to improve the prognosis of the patients. Myeloid-derived suppressor cells (MDSCs), which reveal immunosuppressive in tumor microenvironment via inhibition of CD4+ T cell proliferation [ 25 ], accumulate in tumor cells and peripheral blood as the disease is progressed or in advanced stages of pancreatic cancer [ 26 , 27 , 28 , 29 , 30 ]. Reducing the number of MDSCs is a key antitumor mechanisms of some chemotherapy agents, including 5-FU [ 31 ], which prevents the accumulation of MDSCs in patients with pancreatic cancer [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Severe Neutropenia is Associated with Better Clinical Outcomes in Patients with Advanced Pancreatic Cancer Who Receive Modified FOLFIRINOX Therapy

Yamada

Fujii

Watanabe

et al. 2018

Cancers

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While modified FOLFIRINOX therapy is effective for treating advanced pancreatic cancer, it frequently causes severe neutropenia. The present study investigated the effect of severe neutropenia on clinical outcomes in advanced pancreatic cancer patients who received modified FOLFIRINOX. The study subjects were 51 patients (30 males and 21 females) with advanced pancreatic cancer who received modified FOLFIRINOX (2h bolus injection of oxaliplatin at 85 mg/m2, 2 h bolus injection of L-leucovorin at 200 mg/m2, 90min bolus injection of irinotecan at 150 mg/m2, followed by continuous infusion of 5-fluorouracil for 46 h at 2400 mg/m2 without bolus 5-fluorouracil) during the period from January 2014 to May 2018. No patients had prior history of chemotherapy. Adverse events, including neutropenia, were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. Median overall survival (OS) was the primary endpoint, while median time to treatment failure (TTF), overall response rate (ORR), and the incidence of other adverse events were secondary endpoints. Severe neutropenia (grade ≥3) occurred in 39 patients (76.4%), and Cox proportional hazard analysis identified high total bilirubin level as a significant risk factor. Median duration of OS was significantly longer in patients with severe neutropenia than in those without it (21.3 months versus 8.9 months, p = 0.020). Moreover, there was a significant correlation between OS and the grade of neutropenia (r = 0.306, p = 0.029). ORR tended to be higher, though not significantly, in patients with severe neutropenia. In contrast, the incidence rates of other adverse events were not different between the two groups. Severe neutropenia is an independent predictor of prognosis in advanced pancreatic cancer patients received modified FOLFIRINOX therapy.

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Characterization of Multiple Cytokine Combinations and TGF-β on Differentiation and Functions of Myeloid-Derived Suppressor Cells

Cited by 67 publications

References 29 publications

Mesenchymal stem cell enhances the function of MDSCs in experimental Sjögren syndrome mice

Mesenchymal stem cell enhances the function of MDSCs in experimental Sjögren syndrome mice

Monocytic MDSC as a source of immunosuppressive cytokines in chronic lymphocytic leukemia (CLL) microenvironment

Severe Neutropenia is Associated with Better Clinical Outcomes in Patients with Advanced Pancreatic Cancer Who Receive Modified FOLFIRINOX Therapy

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