scholarly journals Myeloid-Derived Suppressor Cells Regulate Growth of Multiple Myeloma by Inhibiting T Cells in Bone Marrow

2013 ◽  
Vol 190 (7) ◽  
pp. 3815-3823 ◽  
Author(s):  
Indu R. Ramachandran ◽  
Anna Martner ◽  
Alexandra Pisklakova ◽  
Thomas Condamine ◽  
Tess Chase ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
T Cells ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells

Administration Of An Oral PDE5 Inhibitor, Tadalafil In Conjunction With a Lenalidomide Containing Regimen In Patients With Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1959-1959 ◽  
Author(s):  
Nilanjan Ghosh ◽  
Lakshmi Rudraraju ◽  
Xiaobu Ye ◽  
Kimberly Noonan ◽  
Carol Ann Huff ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Flow Cytometry ◽  
T Cells ◽  
Pde5 Inhibitor ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Prior Therapy ◽  
Gi Bleed ◽  
Phosphodiesterase 5

Abstract Increasing tumor burden has been associated with an immunosuppressive network posing a significant barrier to anti-tumor immunity. Amongst these pathways, myeloid derived suppressor cells (MDSCs) play a critical role in suppressing immune function through upregulation of iNOS and arginase-1 (Arg1). There is evidence of increased MDSCs in patients with multiple myeloma compared to healthy donors [1]. Additionally, it has been shown that MDSCs regulate the growth of myeloma by inhibiting T cells in the bone marrow [2]. We therefore hypothesized that inhibiting MDSCs could augment the anti-tumor activity of the immunomodulatory drug lenalidomide. We have shown previously that phosphodiesterase 5 inhibitors such as tadalafil effectively inhibit MDSC function through downregulation of iNOS and Arg-1 production [3]. To prospectively study the effect of MDSC inhibition in myeloma, we initiated a clinical trial in patients who were refractory to lenalidomide-based regimens, with the oral PDE5 inhibitor, tadalafil, added to their lenalidomide-containing regimen. Refractory to lenalidomide containing regimen was defined as disease progression within 60 days of lenalidomide/dexamethasone (Rd) or Biaxin/lenalidomide/dexamethasone (BiRd). Responses were monitored by International Myeloma Working Group (IMWG) criteria. 13 patients were enrolled between April 2012 and March 2013. Median age was 63, 46.1% female, median number of prior therapies was 4 (range 3-10), 10 patients (80%) had BiRd as their immediate prior therapy, 3 (20%) patients had Rd as the immediate prior therapy, 4 (30.8%) patients had high risk cytogenetics/FISH, 4 (30.8%) patients had ISS III disease and 5 (38.4%) patients had a stem cell transplant in the past. 2 patients were not evaluable, 1 did not meet the eligibility criteria and another patient with a history of gastrointestinal (GI) bleed came off protocol in less than a week because of a recurrent GI bleed. 1 (9%) patient had a minor response (MR) lasting 3 months, 4 (36.4%) patients achieved stable disease (SD), 6 (54.5%) patients developed progressive disease (PD). For patients who achieved SD, the median duration was 66 days (range 48-161 days). Median PFS was 48 days (95% CI 25-71 days). 2 (18.1%) patients needed dose reduction of tadalafil for grade 3 back pain, which was the only toxicity attributable to the drug. There were no deaths on study. At a median follow up of 1 year, the OS is 81.8%. The trial met early stopping rule due to lack of response. Biologic correlates were performed pre and post treatment and included measurement of MDSCs numbers by flow cytometry using CD14+, CD33+, HLADRlow, IL4Rα+ or CD15+, CD33+, HLADRlow, IL4Rα+. Interestingly, MDSCs were not detected in any of the patients at baseline in both blood and marrow and this correlated with the lack of clinical response. In mice, lenalidomide can reduce MDSC numbers [4]. All patients on this trial were heavily pre-treated with lenalidomide for a median duration of 783 days (range 55-1741 days) which could explain the low numbers of MDSCs at enrollment. Strategies aimed at inhibiting MDSC function would be best tested in patients who have elevated levels of MDSCs by flow cytometry. References 1. Gorgun, G.T., et al., Tumor-promoting immune-suppressive myeloid-derived suppressor cells in the multiple myeloma microenvironment in humans. Blood, 2013. 121(15): p. 2975-87. 2. Ramachandran, I.R., et al., Myeloid-derived suppressor cells regulate growth of multiple myeloma by inhibiting T cells in bone marrow. J Immunol, 2013. 190(7): p. 3815-23. 3. Serafini, P., et al., Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med, 2006. 203(12): p. 2691-702. 4. Sakamaki, I., et al., Lenalidomide enhances the protective effect of a therapeutic vaccine and reverses immune suppression in mice bearing established lymphomas. Leukemia, 2013. Disclosures: Off Label Use: Tadalafil for supression of myeloid derived suppressor cells.

Increased Population Of Myeloid-Derived Suppressor Cells In Patients With Myelodysplastic Syndromes Overexpress ARG1 and Mediate CD8+ T Cell Inhibition

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5212-5212 ◽  
Author(s):  
Zonghong Shao ◽  
Huijuan Jiang ◽  
Rong Fu
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Myelodysplastic Syndromes ◽  
Suppressor Cells ◽  
Cd8 T Cell ◽  
Myeloid Derived Suppressor Cells ◽  
Normal Controls ◽  
Apoptosis Ratio

Abstract Objective To investigate the proportion and activation of myeloid- derived suppressor cells (MDSC) in bone marrow from patients with myelodysplastic syndromes (MDS). Methods The proportion of MDSC (Lin-HLA-DR-CD33+) in bone marrow of 30 MDS patients and 19 normal controls were measured by flow cytometry assay(FCM). MDSC and CD8+ T cell were isolated from bone marrow of 14 MDS patients and 14 normal controls among them by FCM and microbeads. The expressions of arginase 1(ARG1) and inducible nitric oxide synthase (iNOS) were analyzed by qPCR and western bolting. Co-cultures with CD8+ T cell were proved the MDSC-mediated inhibition of CD8+ T cell. Results MDS patient’s median MDSC were 7.29% which was higher than that of controls (2.91%). The expression of ARG1 and iNOS mRNA in MDSC of high-risk MDS patients was higher than that of low-risk MDS patients. But the protein of ARG1 was overexpressed rather than that of iNOS. After co-cultured, the apoptosis ratio of CD8+ T cells of MDS((64.17±4.86) %) was increased compared to pure CD8+ T cells ( (54.58±9.95)%). Further more, the production of IFN-γsecreted by CD8+ T cells co-cultured with MDSC ((551.94±47.39) pg/ml)was lower than that of pure CD8+ T cells ((586.04±46.65) pg/ml) There was no significant difference in level of TNF-βbetween co-cultured with MDSC and pure CD8+ cells. Conclusion The proportion of MDSC in bone marrow was increased significantly in MDS. MDSC overexpressed ARG1 in patients with MDS and correlated to the malignant degree of this disease. Further more, MDSC can increased the apoptosis ratio of CD8+ T cell, and inhibited the secretion of IFN-γ. These findings suggested MDSC mediated the response of immunosuppression in MDS. Disclosures: No relevant conflicts of interest to declare.

Myeloid-Derived Suppressor Cells in Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2794-2794
Author(s):  
Els Van Valckenborgh ◽  
Jo Van Ginderachter ◽  
Kiavash Movahedi ◽  
Eline Menu ◽  
Karin Vanderkerken
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
T Cell ◽  
Suppressor Cells ◽  
T Cell Responses ◽  
Myeloid Derived Suppressor Cells ◽  
Cell Responses ◽  
T Cell Suppression ◽  
Cell Suppression

Abstract Abstract 2794 Poster Board II-770 Myeloid-derived suppressor cells (MDSCs) are a heterogeneous mix of myeloid cells in different maturation stages generated in the bone marrow. The role of MDSCs in cancer is to suppress T-cell responses, thereby likely regulating tumor progression. In mice, MDSCs are identified by the expression of the surface markers CD11b and Gr-1. Recently, Ly6G+ granulocytic (PMN-MDSC) and Ly6G− monocytic (MO-MDSC) subsets could be distinguished (Movahedi et al. Blood 2008, 111:4233-44). In multiple myeloma patients, the immune function is impaired and this is caused by an immunologically hostile microenvironment and cellular defects, such as decreased numbers of immune cells, and DC or T-cell dysfunction. However, the role of MDSCs in immune suppression in multiple myeloma is not yet described. In this study, we investigated the immunosuppressive activity and mechanism of MDSC subsets in the syngeneic and immunocompetent 5TMM mouse model (5T2 and 5T33 models). In first instance, CD11b+Ly6G− and CD11b+Ly6G+ lineage-committed myeloid MDSC subsets were detected in 5TMM-diseased bone marrow by flow cytometry. These subsets were purified via MACS from the bone marrow of naïve and 5TMM tumor-bearing mice, and analyzed for T-cell suppressive activity. Hereto, CD8+ TCR-transgenic OT-1 splenocytes were stimulated with ovalbumin protein in the presence of purified MDSC subsets, after which T-cell proliferation was measured via 3H-thymidine incorporation. Both MDSC subsets from 5TMM bone marrow were able to suppress antigen-specific T-cell responses at a higher level compared to purified MDSC subsets from normal bone marrow. On average, Ly6G− MDSCs were more suppressive than Ly6G+ MDSCs. The 5T2MM model has a tumor take of approximately 12 weeks. Three weeks after intravenous inoculation of the tumor cells, the suppressive effect of the myeloid subsets was already observed (while the plasmacytosis in the BM was very low and no detectable serum M spike was observed), indicating that T-cell suppression is an early event in MM development. To unravel the suppressive mechanism of the MDSC subsets, inhibitors were used in ovalbumin-stimulated cocultures. Ly6G− MDSC-mediated suppression was partially reversed by the iNOS inhibitor L-NMMA and the COX-2 inhibitor sc-791, both of which lower the NO concentration in culture. In contrast, superoxide dismutase and especially catalase enhance NO concentrations, resulting in enhanced T-cell suppression. None of these inhibitors had any impact on the Ly6G+ MDSC-mediated suppression. In conclusion, these data reveal the presence of MDSCs as a novel immune suppressive strategy employed by multiple myeloma cells in the bone marrow, already occurring early in the disease process. Disclosures: No relevant conflicts of interest to declare.

Increased Frequencies Of Myeloid-Derived Suppressor Cells and Regulatory T-Cells Decrease Response To Donor Lymphocyte Infusions, Independent Of Graft Versus Host Disease In Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2005-2005
Author(s):  
Laurens E. Franssen ◽  
Maarten E. Emmelot ◽  
Niels W.C.J. van de Donk ◽  
Henk Lokhorst ◽  
Tuna Mutis
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Research Funding ◽  
Suppressor Cells ◽  
Cellular Immunotherapy ◽  
Myeloid Derived Suppressor Cells ◽  
Graft Versus Host ◽  
Hla Dr ◽  
Healthy Donors ◽  
Donor Lymphocyte Infusions

Abstract Background Allogeneic stem cell transplantation (allo-SCT) followed by donor lymphocyte infusions (DLI) can induce durable responses in multiple myeloma (MM) by virtue of the graft versus myeloma (GvM) effect. However, this is only true for a minority of patients and relapse rates after reaching an initial remission remain high. Also, transplant-related mortality and Graft-versus-Host-Disease (GvHD) are still major complications. Towards improving cellular immunotherapy we set out to identify the immune cell subsets that are involved in the GvM effect and GvHD. Myeloid-Derived Suppressor Cells (MDSCs) are a heterogeneous population of bone marrow-derived myeloid cells, with strong immunosuppressive capacity. In general, they are divided into monocyte-like M-MDSCs en granulocyte-like G-MDSCs. In myeloma, they have been shown to be present in increased frequencies, inhibit T-cell proliferation and promote multiple myeloma cell growth in vitro. Furthermore, regulatory T-cells (T-regs) seem to suppress cellular anti-tumor responses in MM. Methods To determine whether MDSCs and T-regs hamper immunotherapy, we investigated MDSCs and T-regs in peripheral blood (PB) (n=43) from post-allo SCT MM patients, prior to their first DLI, and from healthy donors (n=13). All patients had persistent or progressive disease after allo-SCT. DLI dose was 107 T-cells/kg for sibling donors (n=20) and 106 T-cells/kg for matched unrelated donors (n=23). Results We observed a significantly higher frequency of M-MDSCs (CD14+ HLA-DR-/low) (mean 5.7 vs. 0.7%, P<0.001) and T-regs (CD4+ CD25+ CD127-/low) (11.4 vs. 5.5%, P<0.01), but not of G-MDSCs (CD11b+ HLA-DR-/low CD14-CD33+) in PB of MM patients versus healthy donors. Interestingly, patients responding to DLI had significantly lower amounts of immunosuppressive G-MDSCs (mean 0.6 vs. 1.2%, P=0.04) and T-regs (7.9 vs. 13.9%, P=0.02) in their PB prior to DLI. There was no difference in M-MDSCs between responding and non-responding patients. This effect on GvM was independent of GvHD, as levels of G-MDSCs, M-MDSCs and T-regs did not differ between GvHD+ and GvHD-groups. Conclusion We show that increased frequencies of G-MDSCs and T-regs are associated with resistance to DLI, independent of the occurrence of GvHD. Our data suggest that targeting G-MDSCs as well as T-regs may improve cellular immunotherapy in multiple myeloma. Disclosures: van de Donk: Celgene: Research Funding. Lokhorst:Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria.

scholarly journals The bone marrow microenvironment enhances multiple myeloma progression by exosome-mediated activation of myeloid-derived suppressor cells

Oncotarget ◽  
2015 ◽  
Vol 6 (41) ◽  
pp. 43992-44004 ◽  
Author(s):  
Jinheng Wang ◽  
Kim De Veirman ◽  
Nathan De Beule ◽  
Ken Maes ◽  
Elke De Bruyne ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Suppressor Cells ◽  
Bone Marrow Microenvironment ◽  
Myeloid Derived Suppressor Cells

scholarly journals A murine Staphylococcus aureus fracture-related infection model characterised by fracture non-union, staphylococcal abscess communities and myeloid-derived suppressor cells

2021 ◽  
Vol 41 ◽  
pp. 774-792
Author(s):  
MI Hofstee ◽  
◽  
M Riool ◽  
F Gieling ◽  
V Stenger ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Bone Marrow ◽  
T Cells ◽  
Cellular Response ◽  
Bone Fractures ◽  
Suppressor Cells ◽  
Infection Model ◽  
Myeloid Derived Suppressor Cells ◽  
Post Surgery ◽  
Over Time

A fracture-related infection (FRI) is a serious complication that can occur after surgical fixation of bone fractures. Affected patients may encounter delayed healing and functional limitations. Although it is well established that Staphylococcus aureus (S. aureus) is the main causative pathogen of an FRI, the pathophysiology of an S. aureus-induced FRI is not well characterised over time. Therefore, an experimental study in mice comparing S. aureus-inoculated and non-inoculated groups was performed that particularly focused on staphylococcal abscess communities (SACs) and host cellular response. C57Bl/6N female mice received a double osteotomy of the femur, which was stabilised using a titanium 6-hole MouseFix locking plate and four screws. Animals were either S. aureus-inoculated or non-inoculated and euthanised between 1 and 28 d post-surgery. Histopathological evaluation showed normal bone healing for non-inoculated mice, whereas inoculated mice had no fracture consolidation and severe osteolysis. Within the bone marrow of inoculated mice, SACs were observed from 7 d, which increased in size and number over time. A fibrin pseudocapsule enclosed the SACs, which were surrounded by many Ly6G+ neutrophils with some Ly6C+ monocytes and F4/80+ macrophages, the majority of which were viable. The abscesses were encapsulated by fibrin(ogen), collagen and myofibroblasts, with regulatory T cells and M2 macrophages at the periphery. Only bone marrow monocytes and neutrophils of inoculated mice displayed functional suppression of T cells, indicative of myeloid-derived suppressor cells. The present study revealed that an FRI in mice is persistent over time and associated with osteolysis, SAC formation and an immunosuppressive environment.

scholarly journals Bendamustine with Total Body Irradiation Limits Murine Graft-Versus-Host Disease in Part Via Myeloid-Derived Suppressor Cells

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2040-2040 ◽  
Author(s):  
Emely Hoffman ◽  
Jessica Stokes ◽  
Megan Stanley Molina ◽  
Emmanuel Katsanis
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Graft Versus Host Disease ◽  
Total Body Irradiation ◽  
Conditioning Regimen ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Myeloablative Conditioning ◽  
Graft Versus Host ◽  
Total Body

Abstract Background GvHD remains a significant challenge in allogeneic hematopoietic cell transplantation (HCT). An under-investigated strategy to reduce GvHD is the modification of the preparative conditioning regimen. Cyclophosphamide (CY) and total body irradiation (TBI) is a commonly utilized myeloablative conditioning regimen, but is associated with GvHD. Bendamustine (BEN) is an alkylating agent that has been applied recently in nonmyeloablative chemotherapy-based conditioning regimens, demonstrating reduced myelosuppression, transplant related mortality, and acute graft versus host disease (GvHD). We have recently published that BEN can effectively replace CY when given following murine haploidentical bone marrow transplantation. We therefore hypothesized that BEN can also have advantages over CY when given in conjunction with TBI as a myeloablative preparative regimen. Methods We used a major histocompatibility mismatched murine BMT model to evaluate GvHD following BEN-TBI and CY-TBI conditioning. BALB/c (H-2d) mice received equivalent doses of BEN or CY (based on maximum tolerated dose), followed by TBI (400 cGy) and infusion of bone marrow (BM) cells with splenocytes (SC) or purified T-cells from C57BL/6 (H-2b) mice. GvHD morbidity and mortality and engraftment were monitored and MDSC frequencies were assessed by flow cytometry and immunofluorescence. Results We demonstrate that BEN-TBI conditioning, while facilitating complete donor chimerism, results in significantly less GvHD and improved survival compared to CY-TBI. In BEN-TBI conditioned mice, suppressive CD11b+Gr-1high myeloid cells are increased in the blood, bone marrow (BM), and spleen, with no evident differences in suppressive function. The ratio of Gr-1+ cells to T-cells is significantly increased in BEN-TBI mice in the intestines. When Gr-1high cells are depleted prior to transplant, the beneficial effects of BEN-TBI are partially lost. Alternatively, administration of G-CSF, which promotes CD11b+Gr-1+ myeloid cell expansion, trends towards an increase in survival in BEN-TBI mice. Conclusions These findings indicate a potential role of granulocytic myeloid-derived suppressor cells (MDSCs) in the mechanism by which BEN allows engraftment with reduced GvHD. BEN-TBI conditioning reduces GvHD morbidity and mortality compared to CY-TBI and may present a safer alternative to CY-TBI as a myeloablative conditioning regimen in allogeneic HCT. Disclosures No relevant conflicts of interest to declare.

scholarly journals Sirt1 Expression Related with Sarcoma Growth after Stem Cell Transplantation Combined with Depletion of Myeloid-Derived Suppressor Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5796-5796
Author(s):  
Ming Li ◽  
Ming Shi ◽  
Yunze Cui ◽  
Yasushi Adachi ◽  
Susumu Ikehara
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Stem Cell ◽  
Conflicts Of Interest ◽  
Malignant Tumors ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Sirt1 Expression ◽  
Cell Transplants ◽  
The Relationship

Abstract Sirtuins (Sirt) play a number of roles in various aging-related diseases such as obesity, diabetes and cancer, and Sirt1 plays a double role in cancer. The combination of bone marrow transplantation (BMT) and thymus transplantation (TT) has been shown to prevent the growth of malignant tumors. Myeloid-derived suppressor cells (MDSCs) can differentiate from bone marrow stem cells under pathological conditions such as cancer, and prevent the potent action of T cells and NK cells, thereby promoting tumor growth. Thus, depleting MDSCs is important when treating cancer. We therefore investigated the relationship between Sirt1 expression and sarcoma growth in sarcoma-bearing mice treated with BMT+TT and the depletion of MDSCs using Gr-1 Ab. Our results showed that only granulocytic MDSCs (G-MDSCs) were depleted by the Gr-1 Ab in these mice. Moreover, the sarcomas decreased significantly in size in the Gr-1 antibody group when compared with the BMT group. This was due to the increase in the percentage of T cells and decrease in the percentage of G-MDSCs. Furthermore, Sirt1 expression decreased significantly in the sarcoma. These findings suggest that inactive Sirt1 may prevent sarcoma growth in sarcoma-bearing mice that receive stem cell transplants and depletion of MDSCs. Disclosures No relevant conflicts of interest to declare.

scholarly journals Monocytic myeloid-derived suppressor cells generated from rhesus macaque bone marrow enrich for regulatory T cells

2018 ◽  
Vol 329 ◽  
pp. 50-55 ◽  
Author(s):  
Alan F. Zahorchak ◽  
Angelica Perez-Gutierrez ◽  
Mohamed B. Ezzelarab ◽  
Angus W. Thomson
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Regulatory T Cells ◽  
Rhesus Macaque ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells
Sign in / Sign up

Export Citation Format

Share Document