scholarly journals Monocytic CCR2+ Myeloid Derived Suppressor Cells Promote Immune Escape by Limiting Activated CD8 T Cell Infiltration Into the Tumor Microenvironment

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2171-2171
Author(s):  
Alexander Lesokhin ◽  
Tobias Hohl ◽  
Taha Merghoub ◽  
Daniel Hirschhorn-cymerman ◽  
Eric G. Pamer ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Immune Escape ◽  
Conflicts Of Interest ◽  
Suppressor Cells ◽  
Cd8 T Cell ◽  
Myeloid Derived Suppressor Cells ◽  
T Effector Cells ◽  
Gm Csf

Abstract Abstract 2171 Myeloid derived suppressor cells (MDSC) are a heterogeneous population of cells that accumulate during tumor progression in a process driven by soluble factors such as granulocyte-macrophage colony stimulating factor (GM-CSF). These cells contribute to the suppressive nature of the tumor microenvironment and interfere with the functions of cytotoxic anti-tumor T effector cells. To date, MDSC heterogeneity has presented a barrier to studying the properties of individual MDSC constituents in vivo. Herein, we find that GM-CSF, a cytokine that promotes the numeric and functional development of monocytes, granulocytes and dendritic cells, and is frequently used as a vaccine adjuvant, is also critical for the expansion of a monocyte-derived MDSC population characterized by the expression of CD11b and the chemokine receptor CCR2. We demonstrate that these cells mediate T cell suppression in a contact dependent fashion and via the function of Arginase and inducible nitric oxide synthase, consistent with known MDSC functions. CD11b+CCR2 negative cells do not have suppressive capability despite also being expanded numerically by the actions of GM-CSF. Utilizing a toxin-mediated ablation strategy that targets CCR2-expressing cells, we demonstrate that monocytic MDSCs regulate activated CD8 T cell entry into the tumor site in vivo, thereby limiting the efficacy of immunotherapy. Our results extend observations on the dual role of GM-CSF in both stimulation and suppression of tumor immunity and suggest therapeutic targeting of monocytic MDSC could enhance the outcomes of immunotherapy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Monocytic CCR2+ Myeloid-Derived Suppressor Cells Promote Immune Escape by Limiting Activated CD8 T-cell Infiltration into the Tumor Microenvironment

2011 ◽  
Vol 72 (4) ◽  
pp. 876-886 ◽  
Author(s):  
Alexander M. Lesokhin ◽  
Tobias M. Hohl ◽  
Shigehisa Kitano ◽  
Czrina Cortez ◽  
Daniel Hirschhorn-Cymerman ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Immune Escape ◽  
Suppressor Cells ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
Myeloid Derived Suppressor Cells ◽  
T Cell Infiltration

scholarly journals Loss of HDAC11 Promotes Myeloid-Derived Suppressor Cells Inhibition of T Cell Function in a Murine Lymphoma Microenvironment

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1105-1105
Author(s):  
Jie Chen ◽  
Fengdong Cheng ◽  
Michael Wang ◽  
Eva Sahakian ◽  
John J. Powers ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Suppressive Activity ◽  
Wild Type ◽  
Murine Lymphoma ◽  
Factor C

Abstract Myeloid-derived suppressor cells constitute a heterogeneous population of immature myeloid cells derived from bone marrow that negatively regulate both innate and adaptive immunity in the tumor microenvironment. Previous work in our lab had demonstrated that MDSCs lacking histone deacetylase 11 (HDAC11) displayed an increase in suppressive activity against IFN-γ producing CD8+ T cells. The upregulated suppressive activity of HDAC11KO MDSCs was associated with a more aggressive tumor growth pattern when compared with wild type control mice. Mechanistically we have found that tumor infiltrated HDAC11KO MDSCs isolated from lymphoma-bearing mice displayed up-regulation of expression and enzymatic activity of arginase 1 and Nos2, two enzymes that are crucial in regulating MDSCs suppressive function, when compare with wild type MDSCs. However, both arginase activity and NO production were at a similar level in the wild type and HDAC11KO MDSCs isolated from spleens of the same lymphoma-bearing mice. This finding suggests that HDAC11KO MDSCs are more suppressive within the tumor microenvironment. Moreover, the aberrant enzymatic activities of Arg1 and Nos2 in HDAC11KO MDSCs correlate with over-expression of the lineage-specific transcription factor C/EBPβ, which has been previously shown to be essential for the differentiation of functional MDSCs. Furthermore, ChIP analysis confirmed that HDAC11 is recruited to the C/EBPβ gene promoter where exerts a negative regulatory effect upon gene transcription. Unlike MDSC's in which absence of HDAC11 is associated with a suppressive phenotype, T-cell lacking HDAC11 are hyper-reactive and endowed with strong antitumor activity. To assess which phenotype will be the dominant one in vivo, we performed adoptive immune cell transfer experiments of both MDSC and/or T-cells from either wild type or HDAC11 KO mice into C57BL/6 lymphoma-bearing animals. The transfer of HDAC11KO MDSCs was able to eliminate, at least partially, the anti-tumor effect elicited by the HDAC11KO T cells in the lymphoma microenvironment Taken together, we have uncovered a previously unknown role for HDAC11 as a transcriptional regulator of MDSCs phenotype and function in a murine lymphoma model. A better understanding of this novel role of HDAC11 in myeloid biology will lead to targeted epigenetic therapies to manipulate the suppressive effect of these immunoregulatory cells in vivo. Disclosures No relevant conflicts of interest to declare.

473 Mavrilimumab, a human monoclonal antibody targeting GM-CSFRα, inhibits polarization to myeloid-derived suppressor cells (MDSCs) that express PD-L1 and restores T-cell proliferation in vitro

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A504-A504
Author(s):  
Luis Carvajal ◽  
Luciana Gneo ◽  
Carmela De Santo ◽  
Matt Perez ◽  
Tracy Garron ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
T Cell ◽  
Cancer Cell ◽  
Suppressor Cells ◽  
T Cell Proliferation ◽  
Myeloid Derived Suppressor Cells ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony

BackgroundMyeloid-derived suppressor cells (MDSCs) accumulate in the blood and tumor microenvironment (TME) and suppress anti-tumor immune responses.1 Cancer cells express the granulocyte-macrophage colony-stimulating factor (GM-CSF), which drives MDSC differentiation and function.2 3 4 It is upregulated in several cancers, including mesothelioma, pancreatic and colorectal, and it is linked to higher levels of intra-tumoral MDSCs and poorer overall survival.2 4 5 In animal models, knockdown of GM-CSF in pancreatic epithelium or pancreatic mesenchymal stem cells inhibits tumorigenesis, reduces intra-tumor MDSCs and enhances CD8+ T cell accumulation.6 7 8 Therefore, targeting the GM-CSF receptor alpha (GM-CSFRα) on MDSCs is an attractive strategy to restore anti-tumor immunity. Mavrilimumab is a clinical stage fully human monoclonal antibody that blocks GM-CSFRα. It has demonstrated efficacy and acceptable safety profile in patients with rheumatoid arthritis, and it’s currently undergoing investigation in phase II studies in giant cell arteritis and in patients with severe COVID-19 pneumonia and hyper-inflammation (NCT03827018, NCT04397497, respectively). The present study investigates its potential as a therapeutic strategy to target MDSCs in the TME as an adjuvant to immunotherapy.MethodsCancer cell supernatants were collected when cells reached confluency. Human GM-CSF was measured by ELISA. Healthy donor CD14+ monocytes were incubated (± mavrilimumab) with cancer cell supernatants for either 3 or 6 days followed by phenotypic analysis (CD14, CD33, HLA-DR, CD11b, CD206, CD80, PD-L1, Arginase-1) by flow cytometry. On day 3, autologous CD3+ T cells were stimulated with CD3/CD28 and IL-2 and co-cultured with putative MDSCs for 5 days. T-cell proliferation was evaluated by measuring carboxyfluorescein succinimidyl ester (CFSE) dilution in CD4+ and CD8+ T cells by flow cytometry.ResultsGM-CSF is expressed in the supernatant of cancer cell lines (HCT116, SW-480, Panc-1, Capan-1). Human monocytes cultured with conditioned medium from colorectal carcinoma (SW-480) or pancreatic adenocarcinoma (Capan-1) show downregulation of HLA-DR, increased expression of PD-L1, Arg-1, CD206, and can suppress T-cell proliferation in-vitro. Similarly, peripheral blood monocytes purified from pancreatic cancer patients suppress T-cell proliferation ex-vivo. Notably, Mavrilimumab inhibits the polarization of healthy donor monocytes to M-MDSCs and restores T-cell proliferation.ConclusionsTargeting of GM-CSFRα with mavrilimumab may alleviate the pro-tumorigenic and immunosuppressive functions of MDSCs in the TME. Future clinical studies should evaluate whether targeting of the GM-CSFRα in combination with immune checkpoint inhibitors is a viable therapeutic option to bolster their efficacy.Ethics ApprovalThe study was approved by the Institute of Immunology and Immunotherapy, University of Birmingham, UK Ethics Board. Healthy volunteer human material was obtained from commercial sources and approved by Stemexpress Institutional Review Board (IRB).ReferencesLaw AMK, Valdes-Mora F, Gallego-Ortega D. Myeloid-Derived Suppressor Cells as a Therapeutic Target for Cancer. Cells 2020;9(3):561.Khanna S, Graef S, Mussai F, et al. Tumor-Derived GM-CSF Promotes Granulocyte Immunosuppression in Mesothelioma Patients. Clin Cancer Res 2018;24(12):2859–2872.Dolcetti L, Peranzoni E, Ugel S, et al. Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF. Eur J Immunol 2010;40(1):22–35.Takeuchi S, Baghdadi M, Tsuchikawa T, et al. Chemotherapy-derived inflammatory responses accelerate the formation of immunosuppressive myeloid cells in the tissue microenvironment of human pancreatic cancer. Cancer Res 2015;75(13):2629–2640.Chen Y, Zhao Z, Chen Y, et al. An epithelial-to-mesenchymal transition-inducing potential of granulocyte macrophage colony-stimulating factor in colon cancer. Sci Rep 2017;7(1):8265.Bayne LJ, Beatty GL, Jhala N, et al. Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 2012;21(6):822–835.Pylayeva-Gupta Y, Lee KE, Hajdu CH, Miller G, Bar-Sagi D. Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 2012;21(6):836–847.Waghray M, Yalamanchili M, Dziubinski M, et al. GM-CSF mediates mesenchymal-epithelial cross-talk in pancreatic cancer. Cancer Discov 2016;6(8):886–899.

scholarly journals ME-10 * TUMOR MICROENVIRONMENT INFILTRATING MYELOID DERIVED SUPPRESSOR CELLS INHIBIT ANTI-TUMOR T CELL RESPONSES

2014 ◽  
Vol 16 (suppl 5) ◽  
pp. v121-v122
Author(s):  
N. Kamran ◽  
M. Ayala ◽  
Y. Li ◽  
H. Assi ◽  
M. Candolfi ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Suppressor Cells ◽  
T Cell Responses ◽  
Myeloid Derived Suppressor Cells ◽  
Cell Responses

Interferon-γ-Induced Myeloid-Derived Suppressor Cells Aggravate Kidney Ischemia-Reperfusion Injury by Regulating Innate Immune Cells

Nephron ◽  
2021 ◽  
pp. 1-11
Author(s):  
Jiawei Ji ◽  
Yuan Zhuang ◽  
Zhemin Lin ◽  
Yihang Jiang ◽  
Wei Wang ◽  
...  
Keyword(s):  
T Cell ◽  
Adoptive Transfer ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Gm Csf ◽  
Ifn Γ ◽  
Cell Functionality

<b><i>Objective:</i></b> Myeloid-derived suppressor cells (MDSCs) are heterogeneous cells which can suppress T-cell functionality. Herein, we evaluated the functional importance of MDSCs in the context of kidney ischemia-reperfusion injury (IRI) and explored their ability to regulate innate and adaptive immune cell function in this context. <b><i>Methods:</i></b> The differentiation of MDSCs was induced in vitro by treating cells with GM-CSF and interferon (IFN)-γ. In a murine model of renal IRI, serum creatinine and blood urea nitrogen values were measured to monitor kidney function, while histopathological and immunohistochemical approaches were used to assess kidney injury severity. In addition, flow cytometry was employed to assess the phenotypes and apoptosis of kidney cells in these mice. <b><i>Results:</i></b> MDSCs induced by treatment with GM-CSF + IFN-γ could suppress T-cell functionality in vitro<i>.</i> The adoptive transfer of these MDSCs into an IRI mouse model system enhanced kidney damage and impaired renal function following the recruitment of these cells to renal tissues in these mice. Following such adoptive transfer, the relative frequency of MDSCs with a CD11b<sup>+</sup>Ly6G<sup>−</sup>Ly6C<sup>high</sup> monocytic-MDSC phenotype decreased, whereas cells with a CD11b<sup>+</sup>Ly6G<sup>+</sup>Ly6C<sup>low</sup> polymorphonuclear-MDSC phenotype become more prevalent within kidney tissues following IRI. Adoptive transfer also coincided with increased frequencies of macrophages and dendritic cells (DCs) in the kidney tissues. This suggested that M-MDSCs contributed to early-stage renal IRI damage by differentiating into these deleterious cell types. However, MDSC-induced suppression of CD4<sup>+</sup> and CD8<sup>+</sup> T-cell infiltration was not sufficient to prevent the deterioration of renal function in these mice. <b><i>Conclusions:</i></b> Herein, we successfully developed a protocol wherein MDSCs were differentiated in vitro through combination GM-CSF/IFN-γ treatment. When these MDSCs were subsequently adoptively transferred into a murine model of renal IRI, they aggravated kidney damage, likely owing to the differentiation of M-MDSCs into deleterious macrophages and DCs.

scholarly journals The GM-CSF–IRF5 signaling axis in eosinophils promotes antitumor immunity through activation of type 1 T cell responses

2020 ◽  
Vol 217 (12) ◽  
Author(s):  
Isabelle C. Arnold ◽  
Mariela Artola-Boran ◽  
Alessandra Gurtner ◽  
Katrin Bertram ◽  
Michael Bauer ◽  
...  
Keyword(s):  
T Cell ◽  
Antitumor Immunity ◽  
Critical Role ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Tumor Control ◽  
Gm Csf ◽  
Cell Responses

The depletion of eosinophils represents an efficient strategy to alleviate allergic asthma, but the consequences of prolonged eosinophil deficiency for human health remain poorly understood. We show here that the ablation of eosinophils severely compromises antitumor immunity in syngeneic and genetic models of colorectal cancer (CRC), which can be attributed to defective Th1 and CD8+ T cell responses. The specific loss of GM-CSF signaling or IRF5 expression in the eosinophil compartment phenocopies the loss of the entire lineage. GM-CSF activates IRF5 in vitro and in vivo and can be administered recombinantly to improve tumor immunity. IL-10 counterregulates IRF5 activation by GM-CSF. CRC patients whose tumors are infiltrated by large numbers of eosinophils also exhibit robust CD8 T cell infiltrates and have a better prognosis than patients with eosinophillow tumors. The combined results demonstrate a critical role of eosinophils in tumor control in CRC and introduce the GM-CSF–IRF5 axis as a critical driver of the antitumor activities of this versatile cell type.

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.

scholarly journals Mechanism of Suppression Effect of Myeloid-Derived Suppressor Cells on Hyperacute Graft-Versus-Host Disease

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5716-5716
Author(s):  
Yigeng Cao ◽  
Ming-Zhe Han ◽  
Peng Liu ◽  
Haiyan Gong ◽  
Haiyan Zhu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Suppressor Cells ◽  
Cd8 T Cell ◽  
Large Sample Size ◽  
Myeloid Derived Suppressor Cells ◽  
Common Complication ◽  
Host Disease ◽  
Graft Versus Host

Abstract Allogeneic HSCT (allo-HSCT) is associated with serious side effects and its most common complication is graft-versus-host disease (GVHD). Hyperacute GVHD is a clinical syndrome that occurs within the first 14 days after allo-HSCT associated with significant morbidity and mortality. The large sample size of clinical study indicated that the incidence of hyperacute GVHD in patient who underwent an allo-HSCT was about 9%, but the pathological process and crucial factor of this complication have incompletely defined. Myeloid-derived suppressor cells (MDSCs) have been found that had a beneficial role in treatment of GVHD, on account of suppressing ability on alloreactive T-cell-response in vitro and in vivo. It was reported that reactive oxygen species (ROS) have been implicated in MDSCs-mediated T cell suppression and MDSCs from NOX2-deficient mice, chronic granulomatous disease (CGD) mice, failed to suppress T cell function. However, the investigation of whether and how MDSCs and ROS play in CGD mice receiving allo-HSCT is lacking. In our research, WT mice receiving allo-HSCT began to appear typical acute GVHD clinical manifestations in about 20 days and died within 30 days after transplantation, while CGD mice receiving allo-HSCT suddenly suffered from hyperacute GVHD at day 3 after allo-HSCT: performed continuous weight loss, demonstrated poor grooming and impairs movement with or without hunching or skin integrated and animals died within 2 days after onset of symptoms. Further study shown that the donor spleen derived T cells was indispensable for hyperacute GVHD of CGD mice after receiving allo-HSCT. T lymphocyte subsets and proportional change in bone marrow and spleen of each group were detected by flow cytommeter after transplantation. The percentage and absolute number of donor derived CD3+CD8+T cell from both BM and spleen of CGD were significant higher than that of WT mice received allo-HSCT. Moreover, cell size and expression of activation marker CD25, CD44, and CD69 of CD3+CD8+T cell from both BM and spleen of CGD mice were significant higher than that of WT mice. The killing ability of donor derived CD3+T cells was observed by the living cells workstation and it was obviously to see that allo-reactive T cells from CGD mice had stronger killing ability. The levels of different cytokines in serum of recipient mice were detected by protein chip at day 3 after allo-HSCT. Comparing to C57BL/6 mice, more than ten kinds of inflammatory factors, including IL-6, were increased in the serum of CGD mice, which indicated that the cytokine storm related to T cells might be occur during hyperacute GVHD. In addition, using this hyperacute mouse model, we revealed that application of ROS agonist, L-buthionine-S, R-sulfoximine (BSO), rescued the CGD mice receiving allo-HSCT from hyperacute GVHD. In General, this study pioneering established a stable murine model of hyperacute GVHD and proved that allo-reactive T cells massively activated and proliferated since ROS production defective MDSCs lose the ability of inhibiting T cell immune reaction and caused hyperacute GVHD. These data provided new insights into the pathogenesis of GVHD and may improve the clinical management of this common complication. Disclosures No relevant conflicts of interest to declare.

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.

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