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

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.

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.

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

scholarly journals NRF2 Is One of the Players Involved in Bone Marrow Mediated Drug Resistance in Multiple Myeloma

2018 ◽  
Vol 19 (11) ◽  
pp. 3503 ◽  
Author(s):  
Chia-Hung Yen ◽  
Hui-Hua Hsiao
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Drug Resistance ◽  
Hematologic Malignancy ◽  
Suppressor Cells ◽  
Resistance Mechanisms ◽  
Bone Marrow Microenvironment ◽  
Myeloma Cells ◽  
Functional Roles ◽  
Oxidative Stresses

Multiple myeloma with clonal plasma expansion in bone marrow is the second most common hematologic malignancy in the world. Though the improvement of outcomes from the achievement of novel agents in recent decades, the disease progresses and leads to death eventually due to the elusive nature of myeloma cells and resistance mechanisms to therapeutic agents. In addition to the molecular and genetic basis of resistance pathomechanisms, the bone marrow microenvironment also contributes to disease progression and confers drug resistance in myeloma cells. In this review, we focus on the current state of the literature in terms of critical bone marrow microenvironment components, including soluble factors, cell adhesion mechanisms, and other cellular components. Transcriptional factor nuclear factor erythroid-derived-2-like 2 (NRF2), a central regulator for anti-oxidative stresses and detoxification, is implicated in chemoresistance in several cancers. The functional roles of NRF2 in myeloid-derived suppressor cells and multiple myeloma cells, and the potential of targeting NRF2 for overcoming microenvironment-mediated drug resistance in multiple myeloma are also discussed.

scholarly journals Novel Therapeutic Approach to Improve Hematopoiesis By Targeting Myeloid Derived Suppressor Cells with a Humanized Anti-CD33 Antibody

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4597-4597
Author(s):  
Erika A Eksioglu ◽  
Karl-Heinz Heider ◽  
Bjoern Rueter ◽  
Alexis Burnette ◽  
Max Wei ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Molecular Genetic ◽  
Suppressor Cells ◽  
Bone Marrow Microenvironment ◽  
Myeloid Derived Suppressor Cells ◽  
Igg Antibody ◽  
Environmental Pressures ◽  
Hematopoietic Stem

Abstract Myelodysplastic syndrome (MDS) is one of the major types of acquired bone marrow failure characterized by impaired peripheral blood cell production (anemia and cytopenias). Although much has been learned regarding the molecular genetic events involved in the pathogenesis of the MDS hematopoietic stem/progenitor cell compartment (HSC/HPC), investigations of the environmental pressures underlying disease initiation have been limited. Prior investigations have shown that inflammation in the bone marrow microenvironment contributes to hematopoietic impairment, with inflammatory molecules providing regulatory cues driving the proliferation and apoptotic death of HSC/HPC. We have reported that, the accumulation of myeloid-derived suppressor cells (MDSCs) in the local inflammatory bone marrow microenvironment plays a major role in the direct pathogenesis of MDS. MDSCs function by producing mediators and inflammatory cytokines capable of suppressing hematopoiesis and are defined by the lack of all lineage markers and only one key surface receptor, CD33 (CD33+HLA-DR−Lin−). We recently uncovered that this receptor is greatly expressed in MDSC isolated from patients with MDS and plays an important role in MDSC-mediated hematopoietic suppressive function. We also found that this ITIM (immune-receptor tyrosine-based inhibitor motif) containing molecule could induce suppressive cytokines after its engagement with its newly identified ligand S100A9. Therefore, we tested the hypothesis that with a fully human IgG1 monoclonal antibody against CD33 (mAb33.1) we could prevent the engagement of this ligand/receptor pair as well as induce ADCC of pathogenic MDSC through the reduction in the accumulation of CD33+ MDSC, the immune suppression and the restoration of hematopoiesis in MDS bone marrow specimens. After testing primary specimens with mAb33.1 we saw a significant increase in ADCC activity via NK as evidenced by significant reduction in the proportion of MDSC in culture as compared to isotype control treated cells. This decrease correlated with an increase in CD107a granule mobilization as well as an increased cytotoxicity in a killing assay without changing the proportion of NK cells in the culture. Functionally, the concentration of secreted IL-10, TGFb and VEGF were decreased, as was the gene expression of these suppressive cytokines after treatment with mAb33.1 but was restored when the antibody was cross-linked with an anti-human IgG antibody demonstrating the blocking ability of the antibody in preventing CD33 downstream signaling. Importantly, all of these observations correlated with the restoration of hematopoiesis, as there was a significant increase in the formation of CFU-GM and BFU-E colonies on a methylcellulose assay (n=9). In addition mAb33.1 also displayed a protective effect on HSC by blocking ROS production and reducing DNA damage, as demonstrated by comet and H2AX assays. This work provides the ground for the development of a novel group of therapies directly aimed at the suppressive MDSC and blockage of their signaling, rather than directly targeting the malignant clone, with the long term goal of improving the local microenvironment. This strategy will provide the background to assess its clinical potential to serve as a therapeutic target in MDS and AML. Disclosures No relevant conflicts of interest to declare.

Exosome-derived miR-let-7c promotes angiogenesis in multiple myeloma by polarizing M2 macrophages in the bone marrow microenvironment

2021 ◽  
Vol 105 ◽  
pp. 106566
Author(s):  
Xiangyu Tian ◽  
Miaomiao Sun ◽  
Han Wu ◽  
Chao Chen ◽  
Hui Li ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Bone Marrow Microenvironment ◽  
M2 Macrophages

Myeloid-derived suppressor cells induce multiple myeloma cell survival by activating the AMPK pathway

2019 ◽  
Vol 442 ◽  
pp. 233-241 ◽  
Author(s):  
Kim De Veirman ◽  
Eline Menu ◽  
Ken Maes ◽  
Nathan De Beule ◽  
Eva De Smedt ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Survival ◽  
Suppressor Cells ◽  
Myeloma Cell ◽  
Myeloid Derived Suppressor Cells ◽  
Multiple Myeloma Cell ◽  
Ampk Pathway
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