scholarly journals IMMU-28. TARGETING IMMUNOSUPPRESSIVE MYELOID DERIVED SUPPRESSOR CELLS VIA MIF/CD74 SIGNALING AXIS TO ATTENUATE GBM GROWTH

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi125-vi125
Author(s):  
Tyler Alban ◽  
Defne Bayik ◽  
Balint Otvos ◽  
Matthew Grabowski ◽  
Manmeet Ahluwalia ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Immune Cell ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Signaling Axis ◽  
Immunosuppressive Microenvironment ◽  
And Function

Abstract The immunosuppressive microenvironment in glioblastoma (GBM) enables persistent tumor growth and evasion from tumoricidal immune cell recognition. Despite a large accumulation of immune cells in the GBM microenvironment, tumor growth continues, and evidence for potent immunosuppression via myeloid derived suppressor cells (MDSCs) is now emerging. In agreement with these observations, we have recently established that increased MDSCs over time correlates with poor prognosis in GBM, making these cells of interest for therapeutic targeting. In seeking to reduce MDSCs in GBM, we previously identified the cytokine macrophage migration inhibitory factor (MIF) as a possible activator of MDSC function in GBM. Here, using a novel in vitro co-culture system to reproducibly and rapidly create GBM-educated MDSCs, we observed that MIF was essential in the generation of MDSCs and that MDSCs generated via this approach express a repertoire of MIF receptors. CD74 was the primary MIF receptor in monocytic MDSCs (M-MDSC), which penetrate the tumor microenvironment in preclinical models and patient samples. A screen of MIF/CD74 interaction inhibitors revealed that MN-166, a clinically relevant blood brain barrier penetrant drug, which is currently fast tracked for FDA approval, reduced MDSC generation and function in vitro. This effect was specific to M-MDSC subsets expressing CD74, and appeared as reduced downstream pERK signaling and MCP-1 secretion. In vivo, MN-166 was able reduce tumor-infiltrating MDSCs, while conferring a significant increase in survival in the syngeneic glioma model GL261. These data provide proof of concept that M-MDSCs can be targeted in the tumor microenvironment via MN-166 to reduce tumor growth and provide a rationale for future clinical assessment of MN-166 to reduce M-MDSCs in the tumor microenvironment. Ongoing studies are assessing the effects of MDSC inhibition in combination with immune activating approaches, in order to inhibit immune suppression while simultaneously activating the immune system.

scholarly journals The critical immunosuppressive effect of MDSC-derived exosomes in the tumor microenvironment

2020 ◽  
Author(s):  
Mohammad H. Rashid ◽  
Thaiz F. Borin ◽  
Roxan Ara ◽  
Raziye Piranlioglu ◽  
Bhagelu R. Achyut ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Cd8 T Cells ◽  
Suppressor Cells ◽  
Cell Types ◽  
Biological Macromolecules

AbstractMyeloid-derived suppressor cells (MDSCs) are an indispensable component of the tumor microenvironment (TME), and our perception regarding the role of MDSCs in tumor promotion is attaining extra layer of intricacy in every study. In conjunction with MDSC’s immunosuppressive and anti-tumor immunity, they candidly facilitate tumor growth, differentiation, and metastasis in several ways that yet to be explored. Alike any other cell types, MDSCs also release a tremendous amount of exosomes or nanovesicles of endosomal origin and partake in intercellular communications by dispatching biological macromolecules. There has not been any experimental study done to characterize the role of MDSCs derived exosomes (MDSC exo) in the modulation of TME. In this study, we isolated MDSC exo and demonstrated that they carry a significant amount of proteins that play an indispensable role in tumor growth, invasion, angiogenesis, and immunomodulation. We observed higher yield and more substantial immunosuppressive potential of exosomes isolated from MDSCs in the primary tumor area than those are in the spleen or bone marrow. Our in vitro data suggest that MDSC exo are capable of hyper activating or exhausting CD8 T-cells and induce reactive oxygen species production that elicits activation-induced cell death. We confirmed the depletion of CD8 T-cells in vivo by treating the mice with MDSC exo. We also observed a reduction in pro-inflammatory M1-macrophages in the spleen of those animals. Our results indicate that immunosuppressive and tumor-promoting functions of MDSC are also implemented by MDSC-derived exosomes which would open up a new avenue of MDSC research and MDSC-targeted therapy.

scholarly journals Glucosamine Interferes With Myelopoiesis and Enhances the Immunosuppressive Activity of Myeloid-Derived Suppressor Cells

2021 ◽  
Vol 8 ◽  
Author(s):  
Eric Chang-Yi Lin ◽  
Shuoh-Wen Chen ◽  
Luen-Kui Chen ◽  
Ting-An Lin ◽  
Yu-Xuan Wu ◽  
...  
Keyword(s):  
Glucose Transporter ◽  
Immune Cell ◽  
Suppressor Cells ◽  
Therapeutic Benefit ◽  
Myeloid Derived Suppressor Cells ◽  
Hematopoietic Stem ◽  
Glucose Transporter 1 ◽  
Arginase 1

Glucosamine (GlcN) is the most widely consumed dietary supplement and exhibits anti-inflammatory effects. However, the influence of GlcN on immune cell generation and function is largely unclear. In this study, GlcN was delivered into mice to examine its biological function in hematopoiesis. We found that GlcN promoted the production of immature myeloid cells, known as myeloid-derived suppressor cells (MDSCs), both in vivo and in vitro. Additionally, GlcN upregulated the expression of glucose transporter 1 in hematopoietic stem and progenitor cells (HSPCs), influenced HSPC functions, and downregulated key genes involved in myelopoiesis. Furthermore, GlcN increased the expression of arginase 1 and inducible nitric oxide synthase to produce high levels of reactive oxygen species, which was regulated by the STAT3 and ERK1/2 pathways, to increase the immunosuppressive ability of MDSCs. We revealed a novel role for GlcN in myelopoiesis and MDSC activity involving a potential link between GlcN and immune system, as well as the new therapeutic benefit.

Myeloid-derived suppressor cells as a potential treatment target for pancreas adenocarcinoma.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 194-194
Author(s):  
M. R. Porembka ◽  
J. B. Mitchem ◽  
P. S. Goedegebuure ◽  
D. Linehan
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Animal Studies ◽  
Suppressor Cells ◽  
Disease Stage ◽  
Tumor Growth Rate ◽  
Myeloid Derived Suppressor Cells ◽  
Pancreas Adenocarcinoma

194 Background: Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immunosuppressive cells that are upregulated in cancer. Little is known about the prevalence and importance of MDSC in pancreas adenocarcinoma (PA). Here, we quantify MDSC prevalence in patients with PA and assess the efficacy of MDSC depletion in a murine model of PA. Methods: Peripheral blood and tumor samples were collected from patients with PA, analyzed for MDSC (CD15+11b+) by flow cytometry (FC) and compared to cancer-free controls (CFC). The suppressive capacity of MDSC and the effectiveness of MDSC depletion were assessed in C57BL/6 mice inoculated with Pan02, a murine PA, and treated with placebo or zoledronic acid (ZA), a potent aminobisphosphonate previously shown to target MDSC. Endpoints included tumor size, survival, and MDSC prevalence. Tumor cell infiltrate was analyzed by FC for MDSC (Gr1+CD11b+) and effector T cells; tumor cytokine levels were measured by Luminex assay. Results: Patients with PA demonstrated increased circulating MDSC compared to CFC, which correlated with disease stage (metastatic PA: 68%±3.6% of CD45+ cells, resectable PA: 57%±3.5%, CFC: 37%±3.6%; p<0.0001). Normal pancreas tissue showed no MDSC infiltrate while PA avidly recruited CD11b+15+ cells to the primary tumor. Murine tumors similarly recruited MDSC that actively suppressed CD8+ T cells in vitro measured by CFSE dilution and accelerated tumor growth in vivo by adoptive transfer with Pan02 cells (p<0.001). Treatment with ZA impaired MDSC accumulation in the tumor (Placebo: 78%, ZA: 51%, p<0.05) resulting in delayed tumor growth rate (p<0.0001) and prolonged median survival (Placebo: 59 days, ZA: 73 days, p<0.05). MDSC blockade increased recruitment of T cells to the tumor (CD4: 4.4%±1.1% vs 12.2%±2.0%, p<0.05; CD8: 3.9%±1.3% vs 10.6%±2.2%, p<0.05) and a more robust type 1 response with increased levels of IFN-g (p<0.05) and decreased levels of IL-10 (p<0.05). Conclusions: MDSC are an important mediator of tumor-induced immunosuppression in PA. Treatment with ZA effectively blocks MDSC accumulation improving anti-tumor response in animal studies. Efforts to block MDSC may represent a novel treatment strategy for PA. [Table: see text]

scholarly journals Heat shock and HSP70 regulate 5-FU-mediated caspase-1 activation in myeloid-derived suppressor cells and tumor growth in mice

2020 ◽  
Vol 8 (1) ◽  
pp. e000478 ◽  
Author(s):  
Thomas Pilot ◽  
Aurélie Fratti ◽  
Chloé Thinselin ◽  
Anaïs Perrichet ◽  
Lucie Demontoux ◽  
...  
Keyword(s):  
Heat Shock ◽  
Tumor Growth ◽  
Antitumor Effect ◽  
Suppressor Cells ◽  
Inflammasome Activation ◽  
Myeloid Derived Suppressor Cells ◽  
Antitumor Effects ◽  
Caspase 1

BackgroundWe have previously shown that 5-fluorouracil (5-FU) selectively kills myeloid-derived suppressor cells (MDSCs) and activates NLRP3 (NOD-leucine rich repeat and pyrin containing protein 3) inflammasome. NLRP3 activation leads to caspase-1 activation and production of IL-1β, which in turn favors secondary tumor growth. We decided to explore the effects of either a heat shock (HS) or the deficiency in heat shock protein (HSP) 70, previously shown to respectively inhibit or increase NLRP3 inflammasome activation in macrophages.MethodsCaspase-1 activation was detected in vitro in MSC-2 cells by western blot and in vivo or ex vivo in tumor and/or splenic MDSCs by flow cytometry. The effects of HS, HSP70 deficiency and anakinra (an IL-1 inhibitor) on tumor growth and mice survival were studied in C57BL/6 WT orHsp70−/−tumor-bearing mice. Finally, Th17 polarization was evaluated by qPCR (Il17a, Rorc) and angiogenic markers by qPCR (Pecam1, Eng) and immunohistochemistry (ERG).ResultsHS inhibits 5-FU-mediated caspase-1 activation in vitro and in vivo without affecting its cytotoxicity on MDSCs. Moreover, it enhances the antitumor effect of 5-FU treatment and favors mice survival. Interestingly, it is associated to a decreased Th17 and angiogenesis markers in tumors. IL-1β injection is able to bypass HS+5-FU antitumor effects. In contrast, inHsp70−/−MDSCs, 5-FU-mediated caspase-1 activation is increased in vivo and in vitro without effect on 5-FU cytotoxicity. InHsp70−/−mice, the antitumor effect of 5-FU was impeded, with an increased Th17 and angiogenesis markers in tumors. Finally, the effects of 5-FU on tumor growth can be restored by inhibiting IL-1β, using anakinra.ConclusionThis study provides evidence on the role of HSP70 in tuning 5-FU antitumor effect and suggests that HS can be used to improve 5-FU anticancer effect.

Myeloid-derived suppressor cells contribute to systemic lupus erythaematosus by regulating differentiation of Th17 cells and Tregs

2016 ◽  
Vol 130 (16) ◽  
pp. 1453-1467 ◽  
Author(s):  
Jianjian Ji ◽  
Jingjing Xu ◽  
Shuli Zhao ◽  
Fei Liu ◽  
Jingjing Qi ◽  
...  
Keyword(s):  
Disease Activity ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Suppressor Cells ◽  
Cell Polarization ◽  
High Disease Activity ◽  
Myeloid Derived Suppressor Cells ◽  
Systemic Lupus ◽  
And Function

Although major advancements have made in investigating the aetiology of SLE (systemic lupus erythaematosus), the role of MDSCs (myeloid-derived suppressor cells) in SLE progression remains confused. Recently, some studies have revealed that MDSCs play an important role in lupus mice. However, the proportion and function of MDSCs in lupus mice and SLE patients are still poorly understood. In the present study, we investigated the proportion and function of MDSCs using different stages of MRL/lpr lupus mice and specimens from SLE patients with different activity. Results showed that splenic granulocytic (G-)MDSCs were significantly expanded by increasing the expression of CCR1 (CC chemokine receptor 1) in diseased MRL/lpr lupus mice and in high-disease-activity SLE patients. However, the proportion of monocytic (M-)MDSCs remains similar in MRL/lpr lupus mice and SLE patients. G-MDSCs produce high levels of ROS (reactive oxygen species) through increasing gp91phox expression, and activated TLR2 (Toll-like receptor 2) and AIM2 (absent in melanoma 2) inflammasome in M-MDSCs lead to IL-1β (interleukin 1β) expression in diseased MRL/lpr mice and high-disease-activity SLE patients. Previous study has revealed that MDSCs could alter the plasticity of Th17 (T helper 17) cells and Tregs (regulatory T-cells) via ROS and IL-1β. Co-culture experiments showed that G-MDSCs impaired Treg differentiation via ROS and M-MDSCs promoted Th17 cell polarization by IL-1β in vitro. Furthermore, adoptive transfer or antibody depletion of MDSCs in MRL/lpr mice confirmed that MDSCs influenced the imbalance of Tregs and Th17 cells in vivo. Our results indicate that MDSCs with the capacity to regulate Th17 cell/Treg balance may be a critical pathogenic factor in SLE.

scholarly journals Astaxanthin Treatment Induces Maturation and Functional Change of Myeloid-Derived Suppressor Cells in Tumor-Bearing Mice

Antioxidants ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 350
Author(s):  
Seong Mun Jeong ◽  
Yeon-Jeong Kim
Keyword(s):  
Mhc Class Ii ◽  
Target Genes ◽  
Suppressor Cells ◽  
Functional Change ◽  
Related Factor ◽  
Mrna Levels ◽  
Myeloid Derived Suppressor Cells ◽  
Antitumor Effects

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells which accumulate in stress conditions such as infection and tumor. Astaxanthin (ATX) is a well-known antioxidant agent and has a little toxicity. It has been reported that ATX treatment induces antitumor effects via regulation of cell signaling pathways, including nuclear factor erythroid-derived 2-related factor 2 (Nrf2) signaling. In the present study, we hypothesized that treatment with ATX might induce maturation of MDSCs and modulate their immunosuppressive activity. Both in vivo and in vitro treatment with ATX resulted in up-regulation of surface markers such as CD80, MHC class II, and CD11c on both polymorphonuclear (PMN)-MDSCs and mononuclear (Mo)-MDSCs. Expression levels of functional mediators involved in immune suppression were significantly reduced, whereas mRNA levels of Nrf2 target genes were increased in ATX-treated MDSCs. In addition, ATX was found to have antioxidant activity reducing reactive oxygen species level in MDSCs. Finally, ATX-treated MDSCs were immunogenic enough to induce cytotoxic T lymphocyte response and contributed to the inhibition of tumor growth. This demonstrates the role of ATX as a regulator of the immunosuppressive tumor environment through induction of differentiation and functional conversion of MDSCs.

scholarly journals P03.20 A murine, myc-driven lymphoma model expressing human CD22 enables testing of targeted therapies and their effects on tumor immune microenvironment

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A30.1-A30
Author(s):  
F Gsottberger ◽  
C Brandl ◽  
S Petkovic ◽  
L Nitschke ◽  
A Mackensen ◽  
...  
Keyword(s):  
Tumor Growth ◽  
B Cell ◽  
Targeted Therapies ◽  
Immune Cell ◽  
Myeloid Cells ◽  
B Cell Lymphoma ◽  
Primary Lymphoma ◽  
Murine Lymphoma

BackgroundThe tumor microenvironment (TME) is composed of various cell types which closely interact via cell cell contacts and cytokines leading to tumor promotion, immune cell inhibition and drug resistance. TME is increasingly recognized for its role in cancer immunotherapies. In B-cell malignancies, myeloid cells play a central role in supporting tumor growth and immune suppression (Roussel et al., 2017, Cancer Immunol Immunother). Despite the importance of a syngeneic TME, preclinical studies with novel drugs have mainly been performed in models lacking a functional immune system. Therefore, we developed an immune competent murine lymphoma model transgenic to human CD22 to study effects of targeted therapies on TME.Materials and MethodsA chimeric CD22 consisting of human extracellular and murine intracellular CD22 (h/mCD22) was introduced in BL6 mice (BL6h/mCD22). Crossbreeding with BL6λ-myc lead to spontaneous development of murine lymphoma that were serially transplanted. Tumor infiltration and TME was characterized by flow cytometry. Mice were treated with Moxetumomab pasudotox, a CD22 targeted immunotoxin and Doxorubicin.ResultsSpontaneously developed tumors in lymphoid organs from BL6h/mCD22 x λ-myc consist of a monomorphic population of h/mCD22+ murine B cells. Three primary lymphoma subclones were isolated from distinct mice and serially transplanted in syngeneic mice. Stable tumor growth was established after subcutaneous (sc) and intravenous (iv) injection. However, TME of sc tumors was infiltrated by less than 1% immune cells, while myc-driven lymphoma in humans usually show substantial immune infiltration. In contrast to sc tumors, systemically growing lymphoma in murine bone marrow (BM) are infiltrated by 30% myeloid cells and 1% T-cells and in murine spleen by 10% and 30%, respectively. Myeloid cells found in these tumors were shown to suppress T cell proliferation in vitro. To test functionality of the h/mCD22 transgene, lymphoma-bearing mice were treated with Moxetumomab, which reduced BM lymphoma infiltration by 20 to 100-fold and infiltration in spleen by 5 to 20-fold in the three lymphoma models. Effects of treatment on TME were analyzed after treatment with Doxorubicin which is known to activate myeloid cells in vivo. Compared to untreated controls, Doxorubicin increased CD11b+ cells in spleen by 1.5-fold. Among these cells, Ly6G+ granulocytic cells increased most substantially.ConclusionsWe established primary, myc-driven h/mCD22+ B-cell lymphoma which stably engraft in syngeneic mice with a TME mimicking myc-driven lymphoma in men. The model responds well to CD22-targeted therapy and Doxorubicin induces expected immunologic changes. Therefore, our unique model provides a platform to test CD22-targeting treatment strategies in an immune competent background.Disclosure InformationF. Gsottberger: None. C. Brandl: None. S. Petkovic: None. L. Nitschke: None. A. Mackensen: None. F. Müller: None.

scholarly journals Tumor-Related Exosomes Contribute to Tumor-Promoting Microenvironment: An Immunological Perspective

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Wuzhen Chen ◽  
Jingxin Jiang ◽  
Wenjie Xia ◽  
Jian Huang
Keyword(s):  
T Cell ◽  
Cell Activation ◽  
Nk Cell ◽  
Immune Surveillance ◽  
Suppressor Cells ◽  
Effector T Cell ◽  
T Cell Apoptosis ◽  
And Function

Exosomes are a kind of cell-released membrane-form structures which contain proteins, lipids, and nucleic acids. These vesicular organelles play a key role in intercellular communication. Numerous experiments demonstrated that tumor-related exosomes (TEXs) can induce immune surveillance in the microenvironment in vivo and in vitro. They can interfere with the maturation of DC cells, impair NK cell activation, induce myeloid-derived suppressor cells, and educate macrophages into protumor phenotype. They can also selectively induce effector T cell apoptosis via Fas/FasL interaction and enhance regulatory T cell proliferation and function by releasing TGF-β. In this review, we focus on the TEX-induced immunosuppression and microenvironment change. Based on the truth that TEXs play crucial roles in suppressing the immune system, studies on modification of exosomes as immunotherapy strategies will also be discussed.

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