To see the other types of publications on this topic, follow the link: Suppressive myeloid cells.
Journal articles on the topic 'Suppressive myeloid cells'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'Suppressive myeloid cells.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Van Valckenborgh, Els, Jo Van Ginderachter, Kiavash Movahedi, Eline Menu, and Karin Vanderkerken. "Myeloid-Derived Suppressor Cells in Multiple Myeloma." Blood 114, no. 22 (November 20, 2009): 2794. http://dx.doi.org/10.1182/blood.v114.22.2794.2794.
Full textAbstract:
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.
2
Joseph, Ann Mary, Dominique Parker, Tarik Hawkins, Nicholas Ciavattone, and Eduardo Davila. "TLR-stimulated T cells acquire resistance to MDSC mediated suppression." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 205.15. http://dx.doi.org/10.4049/jimmunol.198.supp.205.15.
Full textAbstract:
Abstract The immunosuppressive tumor microenvironment presents a significant challenge to developing effective T cell-based cancer immunotherapies. Myeloid-derived suppressor cells (MDSCs), a heterogeneous group of cells, are a major contributor to the suppressive tumor microenvironment. MDSCs are immature myeloid cells that develop in response to chronic inflammation generated by an infection or a tumor. Currently, strategies to block MDSC-mediated suppression generate modest anti-tumor responses. This is in part due to lack of specific markers to target MDSCs and inability to simultaneously inhibit the multitude of suppressive mechanisms employed by MDSCs. Generating tumor-reactive T cells with the capacity to resist MDSC-mediated suppression would help facilitate the production of potent anti-tumor T cell therapies. The activation of the Toll-like receptor-Myeloid differentiation factor 88 (TLR-MyD88) signaling pathway in CD8+ T cells enhances cell proliferation, cytotoxic function, and survival. Our studies show that TLR-stimulated T cells are resistant to MDSC-mediated suppression. MyD88-activated CD8+ T cells co-cultured with tumor-derived MDSCs displayed enhanced proliferation and cytokine production over control T cells. Our future objectives are to understand the molecular mechanisms by which TLR-activated T cells acquire resistance properties and to exploit this knowledge to improve antitumor immune responses by overcoming MDSC-mediated suppression.
3
Parker, Katherine, and Suzanne Ostrand-Rosenberg. "HMGB1: a regulator of myeloid-derived suppressor cell potency? (66.37)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 66.37. http://dx.doi.org/10.4049/jimmunol.186.supp.66.37.
Full textAbstract:
Abstract Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells that accumulate in individuals with cancer and inflammation and play a pivotal role in tumor immunity by suppressing T-cell activation and secreting proinflammatory molecules. The suppressive capacity of MDSC is mediated by immune suppressive factors such as arginase and reactive oxygen species (ROS). Nuclear protein, High Mobility Group Box1 (HMGB1), is present in nearly all cells and is released from myeloid cells as a danger response to sepsis, infection, or arthritis. Its release promotes inflammatory responses. HMGB1 signals through a multitude of receptors including TLR4, which is expressed by MDSC. In contrast to other inflammatory mediators which increase MDSC potency, HMGB1 reduced the suppressive capacity of TLR4(-/-) and wildtype MDSC, and reduced ROS levels in TLR4(-/-) MDSC. These findings suggest that HMGB1 may diminish MDSC function and may lead to new immunotherapeutic uses of HMGB1.
4
Du, Hong, Xinchun Ding, and Cong Yan. "Metabolic reprogramming of myeloid-derived suppressive cells." Oncoscience 4, no. 3-4 (April 28, 2017): 29–30. http://dx.doi.org/10.18632/oncoscience.349.
Full text
5
Oliver, Liliana, Rydell Alvarez, Raquel Diaz, Anet Valdés, Sean H. Colligan, Michael J. Nemeth, Danielle Y. F. Twum, et al. "Mitigating the prevalence and function of myeloid-derived suppressor cells by redirecting myeloid differentiation using a novel immune modulator." Journal for ImmunoTherapy of Cancer 10, no. 9 (September 2022): e004710. http://dx.doi.org/10.1136/jitc-2022-004710.
Full textAbstract:
BackgroundImmune suppression is common in neoplasia and a major driver is tumor-induced myeloid dysfunction. Yet, overcoming such myeloid cell defects remains an untapped strategy to reverse suppression and improve host defense. Exposure of bone marrow progenitors to heightened levels of myeloid growth factors in cancer or following certain systemic treatments promote abnormal myelopoiesis characterized by the production of myeloid-derived suppressor cells (MDSCs) and a deficiency in antigen-presenting cell function. We previously showed that a novel immune modulator, termed ‘very small size particle’ (VSSP), attenuates MDSC function in tumor-bearing mice, which was accompanied by an increase in dendritic cells (DCs) suggesting that VSSP exhibits myeloid differentiating properties. Therefore, here, we addressed two unresolved aspects of the mechanism of action of this unique immunomodulatory agent: (1) does VSSP alter myelopoiesis in the bone marrow to redirect MDSC differentiation toward a monocyte/macrophage or DC fate? and (2) does VSSP mitigate the frequency and suppressive function of human tumor-induced MDSCs?MethodsTo address the first question, we first used a murine model of granulocyte-colony stimulating factor-driven emergency myelopoiesis following chemotherapy-induced myeloablation, which skews myeloid output toward MDSCs, especially the polymorphonuclear (PMN)-MDSC subset. Following VSSP treatment, progenitors and their myeloid progeny were analyzed by immunophenotyping and MDSC function was evaluated by suppression assays. To strengthen rigor, we validated our findings in tumor-bearing mouse models. To address the second question, we conducted a clinical trial in patients with metastatic renal cell carcinoma, wherein 15 patients were treated with VSSP. Endpoints in this study included safety and impact on PMN-MDSC frequency and function.ResultsWe demonstrated that VSSP diminished PMN-MDSCs by shunting granulocyte-monocyte progenitor differentiation toward monocytes/macrophages and DCs with heightened expression of the myeloid-dependent transcription factors interferon regulatory factor-8 and PU.1. This skewing was at the expense of expansion of granulocytic progenitors and rendered the remaining MDSCs less suppressive. Importantly, these effects were also demonstrated in a clinical setting wherein VSSP monotherapy significantly reduced circulating PMN-MDSCs, and their suppressive function.ConclusionsAltogether, these data revealed VSSP as a novel regulator of myeloid biology that mitigates MDSCs in cancer patients and reinstates a more normal myeloid phenotype that potentially favors immune activation over immune suppression.
6
Frosch, Jennifer, Ilia Leontari, and John Anderson. "Combined Effects of Myeloid Cells in the Neuroblastoma Tumor Microenvironment." Cancers 13, no. 7 (April 6, 2021): 1743. http://dx.doi.org/10.3390/cancers13071743.
Full textAbstract:
Despite multimodal treatment, survival chances for high-risk neuroblastoma patients remain poor. Immunotherapeutic approaches focusing on the activation and/or modification of host immunity for eliminating tumor cells, such as chimeric antigen receptor (CAR) T cells, are currently in development, however clinical trials have failed to reproduce the preclinical results. The tumor microenvironment is emerging as a major contributor to immune suppression and tumor evasion in solid cancers and thus has to be overcome for therapies relying on a functional immune response. Among the cellular components of the neuroblastoma tumor microenvironment, suppressive myeloid cells have been described as key players in inhibition of antitumor immune responses and have been shown to positively correlate with more aggressive disease, resistance to treatments, and overall poor prognosis. This review article summarizes how neuroblastoma-driven inflammation induces suppressive myeloid cells in the tumor microenvironment and how they in turn sustain the tumor niche through suppressor functions, such as nutrient depletion and generation of oxidative stress. Numerous preclinical studies have suggested a range of drug and cellular therapy approaches to overcome myeloid-derived suppression in neuroblastoma that warrant evaluation in future clinical studies.
7
Takacs, Gregory, Christian Kreiger, Defang Luo, Guimei Tian, Loic Deleyrolle, and Jeffrey Harrison. "IMMU-21. GLIOMA-DERIVED FACTORS RECRUIT AND INDUCE AN IMMUNE SUPPRESSIVE PHENOTYPE IN BONE MARROW-DERIVED CCR2+ MYELOID CELLS." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii135—vii136. http://dx.doi.org/10.1093/neuonc/noac209.519.
Full textAbstract:
Abstract INTRODUCTION Infiltrating immune-suppressive myeloid cells represent a tumor supportive population that contributes to immune checkpoint inhibitor resistance and poor survival in Glioblastoma (GBM) patients. We have previously characterized monocytic-myeloid derived suppressor cells (M-MDSCs) based on their dual expression of chemokine receptors CCR2 and CX3CR1(CCR2+/CX3CR1+). Genetic and pharmacologic targeting of CCR2, in combination with PD-1 blockade, reduced the percentage of M-MDSCs in the glioma-microenvironment and slowed the progression of KR158 and 005GSC murine gliomas. Additional studies are needed to investigate the chemokines responsible for the tumor recruitment of CCR2+/CX3CR1+ cells and the impact of glioma derived factors on their immune suppressive phenotype. OBJECTIVE Evaluate the effect of glioma derived factors on the migration and suppression of bone marrow CCR2+/CX3CR1+ myeloid cells. METHODS A transwell migration assay was utilized to determine the migratory ability of CCR2+/CX3CR1+ cells to KR158B conditioned in the presence of CCL2 and CCL7 neutralizing antibodies. Ly6G-/GR1+ cells were isolated from bone marrow cultured with KR158B conditioned media and co-cultured with freshly isolated T-cells to examine their immune-suppressive phenotype. RESULTS KR158B gliomas differentially upregulate cytokines including CCL2, IL6, G-CSF, GM-CSF as compared to healthy naive brains. KR158B conditioned media increased the percentage of bone marrow-derived CCR2+/CX3CR1+ cells that are CD11b+, Ly6Chi, and Ly6G-. Bone marrow-derived CCR2+/CX3CR1+ cells expanded in KR158B condition media suppress both CD4+ and CD8+ T cell proliferation. Bone marrow-derived CCR2+/CX3CR1+ cells migrate to recombinant CCL2 and CCL7 as well as KR158B glioma conditioned media. Migration to conditioned media is completely inhibited by the combination of CCL2 and CCL7 neutralizing antibodies. High CCL2 and CCL7 are associated with poor prognosis in human GBM. CONCLUSION Glioma-derived CCL2 and CCL7 mediate migration of CCR2+ myeloid cells into the tumor microenvironment in a redundant manner. Additional glioma-derived factors induce CCR2+/CX3CR1+ myeloid cells to a CD4/8+ T cell suppressive state.
8
Topal Gorgun, Gullu, Hiroto Ohguchi, Teru Hideshima, Yu-Tzu Tai, Noopur Raje, Nikhil C. Munshi, Paul G. Richardson, Jacob P. Laubach, and Kenneth C. Anderson. "Inhibition Of Myeloid Derived Suppressor Cells (MDSC) In The Multiple Myeloma Bone Marrow Microenvironment." Blood 122, no. 21 (November 15, 2013): 3089. http://dx.doi.org/10.1182/blood.v122.21.3089.3089.
Full textAbstract:
Abstract The interaction of myeloma (MM) cells with bone marrow accessory cells induces genomic, epigenomic and functional changes which promote tumor development, progression, cell adhesion mediated-drug resistance (CAM-DR), and immune suppression. As in other cancers, bidirectional interaction between MM cells and surrounding cells regulates tumor development on the one hand, while transforming the BM microenvironment into a tumor promoting and immune suppressive milieu on the other. Recent developments in targeted therapies have indicated that generation of the most effective therapeutic strategies requires not only targeting tumor or stroma cells, but also methods to overcome blockade of anti-tumor immune responses. In addition to lymphoid immune suppressor cells such as regulatory T cells (Treg), distinct populations of myeloid cells such as myeloid derived suppressor cells (MDSC) can effectively block anti-tumor immune responses, thereby representing an important obstacle for immunotherapy. While MDSC are rare or absent in healthy individuals, increased numbers of MDSC have been identified in tumor sites and peripheral circulation. We have recently assessed the presence, frequency and functional characteristics of MDSC in patients with newly diagnosed or relapsed MM compared to MM patients with response and healthy donors. We have identified an increased distinct MDSC population (CD11b+CD14-HLA-DR-/lowCD33+CD15+) with tumor promoting and immune suppressive activity in both PB and BM of MM patients. Moreover, we have shown that lenalidomide (Len) and bortezomib (Bort), either alone or in combination, do not target MDSC in MM microenvironment. Moreover, Bort-induced cytotoxicity against MM cells is abrogated in the presence of MDSCs. In solid tumors, MDSC can be targeted by treatment with the multi-targeted receptor tyrosine kinase inhibitor Sunitinib (Sun), which is therefore an effective combination agent with immunotherapy. We therefore assessed whether MDSC-mediated MM growth and immune suppression in the BM and PB can be targeted by Sun, alone or in combination with Len. We first analysed effect of Sun, alone or in combination with Len, on the tumor promoting role of MDSC versus antigen presenting cells (APC) in MM. APC (CD14+HLA-DR+), mMDSC (monocytic CD11b+CD14+HLA-DR-/lowCD33+) and nMDSCs (neutrophilic CD11b+CD14-HLA-DR-/lowCD33+CD15+) were sorted by flow cytometry from MM-BM or PB and cultured with CFSE labeled MM cell lines (MM1.S, RPMI8226 and OPM1), in the absence or presence of Sun (0.5-3uM) and Len (1uM) alone or in combination. CFSE-flow analysis demonstrated that both mMDSC and nMDSC induced MM cell proliferation compared to MM cells alone (dividing cells 51%) or cultured with APC; and importantly, that Sun significantly inhibited MM cell proliferation even in the presence of MDSC (dividing cells 28%).Importantly, Sun combined with Len further enhanced MM cell cytotoxicity in the presence of MDSC. We further analysed effect of Sun on the BM stroma (BMSC)-induced MM cell growth/proliferation. Sun alone modestly inhibited BMSC-induced MM cell growth, and Len enhanced this effect. We next evaluated Sun effect on MDSC-mediated immune suppression in MM. APC, mMDSC, nMDSC were cultured with CFSE labeled autologous CD3 T cells stimulated with CD3/CD28 for 6 days, in the presence of Sun and Len alone or in combination. CFSE flow analysis demonstrated that Sun significantly reversed MDSC-induced suppression of immune effector cells (CD4 T cells, CD8 T cells and NKT cells). Finally, we determined the effect of Sun on MDSC-associated tumor promoting and immune suppressive cytokines. Flow cytometric intracellular cytokine profiling of MDSC in MM-BM and PB demonstrated that Sun increased IFNg expression, while decreasing TNFa and IL-6 expression in MDSC. Overall our data therefore show that MDSCs are increased in the MM microenvironment and play an important role in MM pathogenesis and immune suppression. They provide the rationale for clinical evaluation of Sunitinib to inhibit the tumor-promoting and immune-suppressive functions of MDSCs and improve patient outcome in MM. Disclosures: Hideshima: Acetylon: Consultancy. Tai:Onyx: Consultancy. Munshi:Celgene: Consultancy; Novartis: Consultancy; Millennium: Consultancy. Richardson:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Johnson & Johnson: Consultancy; Celgene: Consultancy; Millenium: Consultancy. Anderson:acetylon: Equity Ownership; oncopep: Equity Ownership; sanofi aventis: Consultancy; gilead: Consultancy; onyx: Consultancy; celgene: Consultancy.
9
Petersson, Julia, Sandra Askman, Åsa Pettersson, Stina Wichert, Thomas Hellmark, Åsa C. M. Johansson, and Markus Hansson. "Bone Marrow Neutrophils of Multiple Myeloma Patients Exhibit Myeloid-Derived Suppressor Cell Activity." Journal of Immunology Research 2021 (August 6, 2021): 1–10. http://dx.doi.org/10.1155/2021/6344344.
Full textAbstract:
Activated normal density granulocytes (NDGs) can suppress T-cell responses in a similar way as myeloid-derived suppressor cells (MDSCs). In this study, we tested the hypothesis that NDGs from blood and bone marrow of multiple myeloma (MM) patients have the ability to suppress T-cells, as MDSC. MM is an incurable plasma cell malignancy of the bone marrow. Like most malignancies, myeloma cells alter its microenvironment to promote tumor growth, including inhibition of the immune system. We found that MM NDG from the bone marrow suppressed proliferation of T-cells, in contrast to healthy donors. The inhibitory effect could not be explained by changed levels of mature or immature NDG in the bone marrow. Moreover, NDG isolated from the blood of both myeloma patients and healthy individuals could inhibit T-cell proliferation and IFN-γ production. On the contrary to previous studies, blood NDGs did not have to be preactivated to mediate suppressive effects. Instead, they became activated during coculture, indicating that contact with activated T-cells is important for their ability to regulate T-cells. The inhibitory effect was dependent on the production of reactive oxygen species and could be reverted by the addition of its inhibitor, catalase. Our findings suggest that blood NDGs from MM patients are suppressive, but no more than NDGs from healthy donors. However, only bone marrow NDG from MM patients exhibited MDSC function. This MDSC-like suppression mediated by bone marrow NDG could be important for the growth of malignant plasma cells in MM patients.
10
D’Amico, Lucia, Sahil Mahajan, Aude-Hélène Capietto, Zhengfeng Yang, Ali Zamani, Biancamaria Ricci, David B. Bumpass, et al. "Dickkopf-related protein 1 (Dkk1) regulates the accumulation and function of myeloid derived suppressor cells in cancer." Journal of Experimental Medicine 213, no. 5 (April 4, 2016): 827–40. http://dx.doi.org/10.1084/jem.20150950.
Full textAbstract:
Tumor–stroma interactions contribute to tumorigenesis. Tumor cells can educate the stroma at primary and distant sites to facilitate the recruitment of heterogeneous populations of immature myeloid cells, known as myeloid-derived suppressor cells (MDSCs). MDSCs suppress T cell responses and promote tumor proliferation. One outstanding question is how the local and distant stroma modulate MDSCs during tumor progression. Down-regulation of β-catenin is critical for MDSC accumulation and immune suppressive functions in mice and humans. Here, we demonstrate that stroma-derived Dickkopf-1 (Dkk1) targets β-catenin in MDSCs, thus exerting immune suppressive effects during tumor progression. Mice bearing extraskeletal tumors show significantly elevated levels of Dkk1 in bone microenvironment relative to tumor site. Strikingly, Dkk1 neutralization decreases tumor growth and MDSC numbers by rescuing β-catenin in these cells and restores T cell recruitment at the tumor site. Recombinant Dkk1 suppresses β-catenin target genes in MDSCs from mice and humans and anti-Dkk1 loses its antitumor effects in mice lacking β-catenin in myeloid cells or after depletion of MDSCs, demonstrating that Dkk1 directly targets MDSCs. Furthermore, we find a correlation between CD15+ myeloid cells and Dkk1 in pancreatic cancer patients. We establish a novel immunomodulatory role for Dkk1 in regulating tumor-induced immune suppression via targeting β-catenin in MDSCs.
11
Sinha, Pratima, and Suzanne Ostrand-Rosenberg. "Withaferin A, a potent and abundant component of Withania somnifera root extract, reduces myeloid-derived suppressor cell function (P2103)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 170.8. http://dx.doi.org/10.4049/jimmunol.190.supp.170.8.
Full textAbstract:
Abstract Myeloid cells play a crucial role in growth and metastasis of malignant tumors. Tumor infiltrating myeloid cells include myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages. These cells infiltrate into tumor and suppress tumor immunity by their inherent immune suppressive activity which is enhanced by interactions with each other (cross-talk). The root extract of the plant Withania somnifera (WRE) has been reported to reduce tumor cell proliferation and angiogenesis. We hypothesize that WRE or its constituents impact tumor infiltrating myeloid cells and thereby boost anti-tumor immunity. HPLC and MS analysis revealed that Withaferin A (WA) is the most abundant constituent of WRE. A prominent effect of MDSC is their production of IL-10 which increases upon cross-talk with macrophages, promoting type-2 immunity. WA reduces constitutive and cross-talk induced IL-10 secretion from MDSC. Macrophage secretion of IL-6 and TNFa cytokines that are characteristic of M1-type macrophages and that also increase MDSC accumulation and function, are also reduced by WA. Much of the T cell suppressive activity of MDSC is due to MDSC production of reactive oxygen species (ROS), and WA significantly reduces MDSC production of ROS. Thus adjunctive treatment with WA has the potential to concomitantly reduce myeloid cell mediated immune suppression, to polarize immunity towards a tumor-rejecting type I phenotype, and to facilitate the development of anti-tumor immunity.
12
Matta, Benjamin, Brian Rosborough, Lisa Mathews, Quan Liu, Dalia Raich-Regue, Thomson Angus, and Heth Turnquist. "Conditional STAT3-deficiency augments Flt3 ligand-driven myeloid-derived suppressor cell expansion but limits their suppressor function (IRM7P.487)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 126.12. http://dx.doi.org/10.4049/jimmunol.192.supp.126.12.
Full textAbstract:
Abstract Fms-like tyrosine kinase 3 ligand (Flt3L) is a potent hematopoietic growth factor that profoundly expands immunostimulatory dendritic cells (DC). Despite this, the influence of Flt3L on immunoregulatory myeloid-derived suppressor cells (MDSC) has not been described. Since DC and MDSC arise from common myeloid progenitors, and Flt3L-driven DC expansion is STAT3-dependent, we sought to precisely define the role of STAT3 in MDSC downstream of Flt3L signaling. We bred myeloid cell-specific STAT3-deficient mice (LysMCre x STAT3loxP) and administered Flt3L (10 μg/d ip, 10d). Splenic DC (CD11c+) and MDSC (Gr-1+) were isolated by magnetic bead selection. Stimulation and suppression of CD3+ T cell responses was assayed in MLR. As expected, STAT3-deficiency prevented Flt3L-mediated CD11c+ DC expansion. However, we observed an increase in MDSC (CD11b+Gr1+) frequency and absolute numbers in STAT3-deficient mice administered Flt3L. Interestingly, Flt3L-expanded MDSC from STAT3-deficient mice exhibited reduced suppressive capacity against CD3+ T cells in MLR compared to controls. These data identify a previously unappreciated STAT3-independent pathway for MDSC expansion, but reinforce the need for STAT3 signaling for their full suppressive capacity. Likewise, we establish that STAT3 has reciprocal effects on suppressive MDSC and immunostimulatory DC expansion. Together, these findings enhance understanding of the immunomodulatory properties of Flt3L.
13
Jung, Minho, and Eun Young Choi. "TLR5 and TLR7 amplify different stage of myeloid cells." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 126.40. http://dx.doi.org/10.4049/jimmunol.202.supp.126.40.
Full textAbstract:
Abstract Balance between immune activation and immune suppression is important for immune homeostasis. Toll-like receptors (TLRs) play key roles in the innate immune system, initiating inflammatory responses against pathogen infections and internal danger signals. Different TLRs recognize different kinds of ligands, but not all the TLRs do have same effect: some TLRs are immune stimulatory, while the others are immune suppressive. For instance, TLR5 ligand has been known to be immune suppressive, while TLR7 ligand has been used for immune activation. To understand how these TLR ligands lead to opposite immune outcomes, we investigated the effects of the ligands on myeloid cell differentiation. Treatment of TLR5 ligand flagellin resulted in the increase of CD11b+ Ly6C+Ly6G+ myeloid-derived suppressor cells (MDSCs) on days 2 and 3 after culture initiation. However, TLR7 ligand gardiquimod led to enhancement of dendritic cell differentiation on day 1, and then increase of CD11c− MHCII− CD11b− Ly6C− Ly6G− progenitor population on day 2, which differentiate into CD11c− MHCIIow CD11b+ Ly6C+ cells with DC differentiation potential afterwards. Based on these results, we suggest that different immune outcomes of TLR ligands would depend on the stages of myeloid cells at which corresponding TLRs act, contributing to overall immune homeostasis.
14
Dong, Juan, Cassandra Gilmore, Hieu Ta, Keman Zhang, Sarah Stone, and Li Wang. "501 VISTA regulates the differentiation and suppressive function of myeloid-derived suppressor cells." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A536. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0501.
Full textAbstract:
BackgroundV-domain immunoglobulin suppressor of T cell activation (VISTA) is a B7 family inhibitory immune checkpoint protein and is highly expressed on myeloid cells and T cells.1 VISTA acts as both an inhibitory ligand when expressed on antigen-presenting cells and a receptor when expressed on T cells. Our recent study has shown that VISTA is a myeloid cell-specific immune checkpoint and that blocking VISTA can reprogram suppressive myeloid cells and promote a T cell-stimulatory tumor microenvironment.2 In this study, we further demonstrate that VISTA blockade directly alters the differentiation and the suppressive function of myeloid-derived suppressor cells (MDSC).MethodsFlow cytometry was performed to examine VISTA expression on MDSCs in multiple murine tumor models including the B16BL6 melanoma model, MC38 colon cancer model, and the KPC pancreatic cancer models. To examine the role of VISTA in controlling the differentiation and suppressive function of MDSCs, we cultured wild type (WT) and VISTA.KO bone marrow progenitor cells with GM-CSF and IL-6 to induce BM -derived MDSCs.ResultsOur preliminary results show that VISTA is highly expressed on M-MDSCs in B16BL6, MC38 and KPC tumors. In BM-derived MDSCs, VISTA deletion significantly altered the signaling pathways and the differentiation of MDSCs. Multiple inflammatory signaling pathways were downregulated in VISTA KO MDSCs, resulting in decreased production of cytokines such as IL1 and chemokines such as CCL2/4/9, as well as significantly impaired their ability to suppress the activation of CD8+ T cells. The loss of suppressive function in VISTA KO MDSCs is correlated with significantly reduced expression of iNOS. To validate the results from BM-MDSCs, we sorted CD11b+CD11c-Ly6C+Ly6G- M-MDSCs and CD11b+CD11c-Ly6G+ G-MDSCs from B16BL6 tumor tissues and tested the ability of a VISTA-blocking mAb to reverse the suppressive effects of tumor-derived MDSCs. Our results show that blocking VISTA impaired the suppressive function of tumor-derived M-MDSC but not G-MDSCs.ConclusionsTaken together, these results demonstrate a crucial role of VISTA in regulating the differentiation and function of MDSCs, and that blocking VISTA abolishes MDSC-mediated T cell suppression, thereby boosting.Ethics ApprovalAll in vivo studies were reviewed and approved by Institutional Animal Care and Use Committee (Approval number 2019-2142).ReferencesXu W, Hire T, Malarkannan, S. et al. The structure, expression, and multifaceted role of immune-checkpoint protein VISTA as a critical regulator of anti-tumor immunity, autoimmunity, and inflammation. Cell Mol Immunol 2018;15:438–446.Xu W, Dong J, Zheng Y, et al. Immune-checkpoint protein VISTA regulates antitumor immunity by controlling myeloid cell-mediated inflammation and immunosuppression. Cancer Immunol Res 2019;7:1497–510.
15
Xiong, Jia, Hui Wang, and Qingqing Wang. "Suppressive Myeloid Cells Shape the Tumor Immune Microenvironment." Advanced Biology 5, no. 3 (February 11, 2021): 1900311. http://dx.doi.org/10.1002/adbi.201900311.
Full text
16
Zeng, Dong, Haixia Long, and Bo Zhu. "Antitumor effects of targeting myeloid-derived suppressive cells." Translational Cancer Research 9, no. 9 (September 2020): 5787–97. http://dx.doi.org/10.21037/tcr.2020.01.52.
Full text
17
Chen, Siqi, Yi Zhang, and Bin Zhang. "MicroRNA-155 regulates tumor myeloid-derived suppressive cells." Oncoscience 2, no. 11 (November 19, 2015): 910–11. http://dx.doi.org/10.18632/oncoscience.269.
Full text
18
Sica, Antonio, Laura Strauss, Francesca Maria Consonni, Cristina Travelli, Armando Genazzani, and Chiara Porta. "Metabolic regulation of suppressive myeloid cells in cancer." Cytokine & Growth Factor Reviews 35 (June 2017): 27–35. http://dx.doi.org/10.1016/j.cytogfr.2017.05.002.
Full text
19
Filipazzi, P., R. Valenti, V. Huber, M. Iero, L. Pilla, G. Parmiani, M. Santinami, and L. Rivoltini. "Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients and modulation by GM-CSF-based anti-tumor vaccine." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 21082. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.21082.
Full textAbstract:
21082 Background: Phenotypic and functional features of myeloid suppressor cells (MSC), known to serve as critical regulators of anti-tumor T cell responses in tumor-bearing mice, are still poorly defined in human cancers. Here we analyzed myeloid subsets with suppressive activity present in peripheral blood of metastatic melanoma patients (MM) and evaluated their modulation by a GM-CSF-based anti- tumor vaccine. Methods: Stage IV AJCC MM patients (n=16) vaccinated with autologous tumor-derived heat-shock protein peptide complexes gp96 (HSPPC-96) and low dose GM-CSF provided pre- and post-treatment whole blood samples. Peripheral blood mononuclear cells (PBMC) were analyzed by flow cytometry, separated into cellular subsets and used for in vitro proliferation assays. PBMC from stage- matched melanoma patients (n=12) treated with non-GM-CSF-based vaccines (i.e. HSPPC-96 alone or IFNa/melanoma-derived peptides) or gender and age-matched healthy donors (n=16) were also analyzed for comparison. Results: The lack or low levels of HLA-DR expression was found to identify a CD14+ cell subset with high suppressive activity on lymphocyte proliferation and functions. CD14+HLA-DR-/lo cells were significantly expanded in all MM patients, while undetectable in healthy donors. Suppressive activity was mediated by TGFβ, as suggested by functional experiments with neutralizing specific antibodies. In contrast, no involvement of arginase and iNOS pathways could be detected. CD14+HLA-DR-/lo cells, as well as spontaneous ex- vivo release and plasma levels of TGFβ, were augmented after administration of the HSPPC-96/GM-CSF vaccine. Interestingly, the expansion of suppressive CD14+ monocytes was associated to the inability to mount a significant CD8-mediated T cell response upon vaccination. On the other hand, no quantitative or qualitative enhancement of the CD14+HLA-DR-/lo suppressive cell population was observed in patients receiving a non-GM-CSF based vaccine. Conclusions: CD14+HLA-DR- /lo cells exerting TGFβ-mediated immune suppression may represent a new subset of myeloid suppressive cells, potentially expandable by the administration of GM-CSF-based vaccines in melanoma patients. [Table: see text]
20
Passioura, Toby, Alla Dolnikov, Sylvie Shen, and Geoff Symonds. "N-Ras–Induced Growth Suppression of Myeloid Cells Is Mediated by IRF-1." Cancer Research 65, no. 3 (February 1, 2005): 797–804. http://dx.doi.org/10.1158/0008-5472.797.65.3.
Full textAbstract:
Abstract Activating mutations in ras oncogenes occur at high frequency in human malignancies and expression of activated ras in immortalized cells lines is generally transforming. However, somewhat paradoxically, ectopic expression of ras in some myeloid cell lines has been shown to induce growth suppression associated with up-regulation of the cyclin-dependent kinase inhibitor p21CIP1/WAF1 in a p16INK4a, p15INK4b, and p53 independent fashion. We have used cDNA array technology to compare the expression profile induced by activated N-ras (N-rasG13R) in growth-suppressed myeloid cells with that induced in myeloid cells, which are transformed by N-rasG13R. The expression profile induced in growth suppressed cells was consistent with differentiation and included the up-regulation of the transcription factor IFN regulatory factor-1 (IRF-1), a known transcriptional activator of p21CIP/WAF1 expression and a target of oncogenic mutations associated with myeloid leukemia. Antisense suppression of IRF-1 prevented N-rasG13R–associated growth arrest and up-regulation of p21CIP1/WAF1. These results define a novel tumor suppressive response to oncogenic signaling and provide a mechanistic link between growth suppression and differentiation in myeloid cells.
21
Haverkamp., Jessica, and Timothy Ratliff. "Regulatory function of myeloid-derived suppressor cells is restricted to inflammatory site. (98.25)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 98.25. http://dx.doi.org/10.4049/jimmunol.184.supp.98.25.
Full textAbstract:
Abstract Myeloid-derived suppressor cells (MDSC) are identified in mice as Gr-1+CD11b+ cells able to suppress T cell proliferation. Suppressive function of MDSC is linked to expression of arginase I and inducible nitric oxide synthase (iNOS) and can be augmented by inflammation. While inflammation is linked to MDSC function, it is unknown if MDSC isolated from the inflammatory site possess equal regulatory function as those in distal sites such as the spleen. Using the POET-3 model of prostate inflammation, we show Gr-1+CD11b+ cells isolated from inflamed prostates express elevated levels of ARG I and iNOS. In contrast, cells from the spleens of mice with prostate inflammation do not express detectable levels of ARG I or iNOS. However, when function of Gr-1+CD11b+ cells from spleens or the inflammatory site were tested in conventional suppression assays, all cells demonstrated suppressive function. RT-PCR analysis revealed that arginase I and iNOS mRNA were induced in MDSC during suppression assays, in part through IFN-γ. Thus conventional suppression assays induce functional suppressor cells and do not test their actual activation state in vivo. To better evaluate the function of Gr-1+CD11b+ cells we developed a short term suppression assay designed to limit exposure to IFN-γ during culture. Only cells from the inflammatory site suppressed T cell proliferation. These data demonstrate the novel finding that only Gr-1+CD11b+ cells at the inflammatory site are functional MDSC.
22
Thakuri, Bal Krishna Chand, Jinyu Zhang, Juan Zhao, Lam N. Nguyen, Lam N. T. Nguyen, Madison Schank, Sushant Khanal, et al. "HCV-Associated Exosomes Upregulate RUNXOR and RUNX1 Expressions to Promote MDSC Expansion and Suppressive Functions through STAT3–miR124 Axis." Cells 9, no. 12 (December 18, 2020): 2715. http://dx.doi.org/10.3390/cells9122715.
Full textAbstract:
RUNX1 overlapping RNA (RUNXOR) is a long non-coding RNA and plays a pivotal role in the differentiation of myeloid cells via targeting runt-related transcription factor 1 (RUNX1). We and others have previously reported that myeloid-derived suppressor cells (MDSCs) expand and inhibit host immune responses during chronic viral infections; however, the mechanisms responsible for MDSC differentiation and suppressive functions, in particular the role of RUNXOR–RUNX1, remain unclear. Here, we demonstrated that RUNXOR and RUNX1 expressions are significantly upregulated and associated with elevated levels of immunosuppressive molecules, such as arginase 1 (Arg1), inducible nitric oxide synthase (iNOS), signal transducer and activator of transcription 3 (STAT3), and reactive oxygen species (ROS) in MDSCs during chronic hepatitis C virus (HCV) infection. Mechanistically, we discovered that HCV-associated exosomes (HCV-Exo) can induce the expressions of RUNXOR and RUNX1, which in turn regulates miR-124 expression via STAT3 signaling, thereby promoting MDSC differentiation and suppressive functions. Importantly, overexpression of RUNXOR in healthy CD33+ myeloid cells promoted differentiation and suppressive functions of MDSCs. Conversely, silencing RUNXOR or RUNX1 expression in HCV-derived CD33+ myeloid cells significantly inhibited their differentiation and expressions of suppressive molecules and improved the function of co-cultured autologous CD4 T cells. Taken together, these results indicate that the RUNXOR–RUNX1–STAT3–miR124 axis enhances the differentiation and suppressive functions of MDSCs and could be a potential target for immunomodulation in conjunction with antiviral therapy during chronic HCV infection.
23
Charles, Julia, Lih-Yun Hsu, Erene Niemi, Arthur Weiss, and Mary Nakamura. "CD11blo Gr1+ osteoclast precursors are increased in inflammatory arthritis and have myeloid derived suppressor cell function. (148.1)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 148.1. http://dx.doi.org/10.4049/jimmunol.186.supp.148.1.
Full textAbstract:
Abstract We have identified a CD11blo Gr1+ bone marrow population of osteoclast precursors (OCP). This population is further defined by the markers Ly6Chi CX3CR1+ CCR2+ CD117- CD11c- and is distinct from previously characterized myeloid precursors and monocyte subsets, suggesting that osteoclasts derive from a distinct precursor analogous to the common dendritic cell precursor. OCP increase in inflammatory arthritis in mice and humans. We find that CD11blo Ly6Chi OCP increase significantly prior to the development of synovitis in zymosan-induced SKG arthritis and remain elevated throughout the course of disease. Like the OCP we identified, monocytic myeloid derived suppressor cells (M-MDSC) are Ly6Chi. We tested our OCP for suppressive activity in vivo using an adoptive transfer model of SKG arthritis. Co-transfer of OCP with SKG CD4+ T-cells into RAG-/- recipients significantly decreased development of inflammatory arthritis compared to transfer of CD4+ T-cells alone, although less dramatically than co-transfer of CD4+ T-cells with wild-type Treg cells. We tested for in vitro suppression of T-cell proliferation by OCP and found that CD11blo Ly6Chi OCP suppress both CD4+ and CD8+ T-cell proliferation. Suppression by OCP is dependent on IFNγ and NOS2, similar to the mechanism described for M-MDSC. Our findings suggest that a myeloid precursor population with both T-cell suppressive activity and the potential to become osteoclasts is expanded in inflammatory arthritis.
24
Aykut, Berk, Ruonan Chen, Jacqueline I. Kim, Dongling Wu, Sorin A. A. Shadaloey, Raquel Abengozar, Pamela Preiss, et al. "Targeting Piezo1 unleashes innate immunity against cancer and infectious disease." Science Immunology 5, no. 50 (August 21, 2020): eabb5168. http://dx.doi.org/10.1126/sciimmunol.abb5168.
Full textAbstract:
Piezo1 is a mechanosensitive ion channel that has gained recognition for its role in regulating diverse physiological processes. However, the influence of Piezo1 in inflammatory disease, including infection and tumor immunity, is not well studied. We postulated that Piezo1 links physical forces to immune regulation in myeloid cells. We found signal transduction via Piezo1 in myeloid cells and established this channel as the primary sensor of mechanical stress in these cells. Global inhibition of Piezo1 with a peptide inhibitor was protective against both cancer and septic shock and resulted in a diminution in suppressive myeloid cells. Moreover, deletion of Piezo1 in myeloid cells protected against cancer and increased survival in polymicrobial sepsis. Mechanistically, we show that mechanical stimulation promotes Piezo1-dependent myeloid cell expansion by suppressing the retinoblastoma gene Rb1. We further show that Piezo1-mediated silencing of Rb1 is regulated via up-regulation of histone deacetylase 2. Collectively, our work uncovers Piezo1 as a targetable immune checkpoint that drives immunosuppressive myelopoiesis in cancer and infectious disease.
25
Takacs, Gregory P., Julia S. Garcia, Caitlyn A. Hodges, Christian J. Kreiger, Alexandra Sherman, and Jeffrey K. Harrison. "CSF1R Ligands Expressed by Murine Gliomas Promote M-MDSCs to Suppress CD8+ T Cells in a NOS-Dependent Manner." Cancers 16, no. 17 (September 1, 2024): 3055. http://dx.doi.org/10.3390/cancers16173055.
Full textAbstract:
Glioblastoma (GBM) is the most common malignant primary brain tumor, resulting in poor survival despite aggressive therapies. GBM is characterized by a highly heterogeneous and immunosuppressive tumor microenvironment (TME) made up predominantly of infiltrating peripheral immune cells. One significant immune cell type that contributes to glioma immune evasion is a population of immunosuppressive cells, termed myeloid-derived suppressor cells (MDSCs). Previous studies suggest that a subset of myeloid cells, expressing monocytic (M)-MDSC markers and dual expression of chemokine receptors CCR2 and CX3CR1, utilize CCR2 to infiltrate the TME. This study evaluated the mechanism of CCR2+/CX3CR1+ M-MDSC differentiation and T cell suppressive function in murine glioma models. We determined that bone marrow-derived CCR2+/CX3CR1+ cells adopt an immune suppressive cell phenotype when cultured with glioma-derived factors. Glioma-secreted CSF1R ligands M-CSF and IL-34 were identified as key drivers of M-MDSC differentiation while adenosine and iNOS pathways were implicated in the M-MDSC suppression of T cells. Mining a human GBM spatial RNAseq database revealed a variety of different pathways that M-MDSCs utilize to exert their suppressive function that is driven by complex niches within the microenvironment. These data provide a more comprehensive understanding of the mechanism of M-MDSCs in glioblastoma.
26
Rajan, Priyanka, Robert Zollo, Mackenzie Lieberman, Yanqi Guo, Mohammed Alruwaili, Mohammed Alqarni, Brian Morreale, et al. "Abstract 5536: The role of p38 MAPK in the tumor-induced immune suppressive microenvironment in metastatic breast cancer." Cancer Research 84, no. 6_Supplement (March 22, 2024): 5536. http://dx.doi.org/10.1158/1538-7445.am2024-5536.
Full textAbstract:
Abstract The tumor microenvironment (TME) in Metastatic Breast Cancer (MBC) is a major factor contributing to therapy resistance and suppression of antitumor immune response. Tumors promote expansion and recruitment of immune suppressive cells such as myeloid-derived suppressor cells (MDSCs) contributing to tumor invasion and suppressing anti-tumor T cells. Our prior work suggested a critical role of p38 MAPK in tumor-induced expansion and mobilization of myeloid cell populations thereby facilitating metastasis. The current study examined the role of p38 MAPK in tumor-induced changes in immune landscape and explored the mechanisms by which p38 mediates tumor-immune interactions. First, the contribution of T cells to anti-metastatic activity of p38 inhibitor (p38i) was addressed by depletion of CD8 T cells. Depletion of CD8+ T cells negated the effects of p38i on tumor growth and metastasis in the syngeneic 4T1 model. Next, we examined whether p38i exhibits a direct effect on T cells in vitro or in vivo. The in vitro assays showed that p38 blockade increased levels of CD44+ CD62L+ CD8+ T cells indicating enhancement of T cell differentiation. To determine the effects of p38 blockade on the immune landscape in vivo, single-cell RNA-seq and flow cytometry studies were performed in the 4T1 model with p38i or p38-deficient cells in which p38α/Mapk14 was inactivated by CRISPR/Cas9 (p38KO). The scRNA-seq data showed that p38 blockade increased the expression of T cell differentiation markers in the TME. Furthermore, p38 blockade significant decreased IL-6 signaling in myeloid cells, an important mediator of MDSC function. Assessment of myeloid cell populations showed a decreased expression of the immune suppressive signature. This observation was further validated in MDSCs isolated from the spleens of 4T1 tumor-bearing mice treated with p38i and in p38KO cohorts. Our prior work showed that p38i does not affect the generation of MDSCs in vitro. Therefore, we examined whether blockade of p38 affects the chemotactic capacity of conditioned media from MBC cells using mouse monocytes. The chemotaxis assays showed that p38i and p38KO largely reduced the ability of conditioned media to stimulate transwell migration of mouse monocytes. Notably, p38i and p38KO largely reduced expression of chemotactic cytokines in MBC cell models. Furthermore, p38i and p38KO reduced production and chemotactic ability of exosomes isolated from tumor cells. Together, these observations suggest that tumor p38 MAPK signaling promotes immune-suppressive TME and metastasis by facilitating expansion and mobilization of myeloid cell populations through the mechanisms involving production of exosomes and pro-myeloid chemokines/cytokines. This work highlights that p38 blockade can be utilized in combination with immune therapy or chemotherapy to enhance clinical benefits of immune therapy and reduce promyeloid effects of chemotherapy. Citation Format: Priyanka Rajan, Robert Zollo, Mackenzie Lieberman, Yanqi Guo, Mohammed Alruwaili, Mohammed Alqarni, Brian Morreale, Scott Olejniczak, Joseph Barbi, Scott Abrams, Andrei Bakin. The role of p38 MAPK in the tumor-induced immune suppressive microenvironment in metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5536.
27
Wieboldt, Ronja, Andreas Zingg, Emanuele Carlini, Anastasiya Börsch, Heinz Läubli, and Natalia Rodrigues Manutano. "Abstract 1259: Disturbing the Siglec-Sialoglycan axis to target myeloid- derived suppressor cells in the tumor microenvironment." Cancer Research 83, no. 7_Supplement (April 4, 2023): 1259. http://dx.doi.org/10.1158/1538-7445.am2023-1259.
Full textAbstract:
Abstract Background: Overexpression of sialic acids on glycans, called hypersialylation is a common alteration in cancer that drives immune evasion via interaction with Sialic acid-binding immunoglobulin-like lectin (Siglec) immunoregulatory receptors on tumor-infiltrating immune cells. Myeloid derived suppressor cells (MDSCs) generated by cancer-induced aberrant myelopoiesis are highly immunosuppressive cells inhibiting immune cells via direct interaction or secretion of suppressive cytokines. Targeting the complex suppressive tumor microenvironment (TME) remains a challenge. Methods: Siglec expression of murine and human MDSCs in healthy conditions and tumor setting was assessed by flow cytometry. Functional analysis of Siglec-E knockout on MDSCs in mice was evaluated using SigE-LysMCre mice and suppressive capacity was tested in vitro in combination with SiglecE blocking and cleavage of Sialoglycans using Sialidase. Results were confirmed in the human setting using an in vitro assay to generate MDSC-like cells including RNA-Sequencing and a MDSC suppression assay with cancer-derived MDSCs. Results: MDSCs express multiple inhibitory Siglec receptors in humans and mice. Knockout of SiglecE in the myeloid compartment in vivo resulted in prolonged survival and increased T cell infiltration compared to litter mates expressing Siglec-E. Of note, desialylation of MDSCs and Siglec-E blocking in vitro reduced MDSCs suppressive function against T cells. Similarly, reducing Sialoglycans by Sialidase in human MDSC generated in vitro resulted in increased suppressive capacity and downregulation of functional MDSC markers on RNA level. Findings were validated with lung cancer patient derived MDSCs. Conclusion: Our results provide first insights into the importance of the Siglec-Sialoglycans axis to modulate MDSCs in the TME. Targeting glycosylation of MDSCs with Sialidase reduces their suppressive capacity making it a powerful approach to improve cancer immunotherapy. Further studies are needed to reveal the underlying mechanisms. Citation Format: Ronja Wieboldt, Andreas Zingg, Emanuele Carlini, Anastasiya Börsch, Heinz Läubli, Natalia Rodrigues Manutano. Disturbing the Siglec-Sialoglycan axis to target myeloid- derived suppressor cells in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1259.
28
Antignano, Frann, Melisa Hamilton, Carla Cohen, Victor Ho, and Gerald Krystal. "SHIP-deficient dendritic cells suppress T cell proliferation via a nitric oxide independent mechanism (91.9)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 91.9. http://dx.doi.org/10.4049/jimmunol.182.supp.91.9.
Full textAbstract:
Abstract Dendritic cells (DCs) are potent stimulators of the immune system but can also be powerful inducers of tolerance. Previous studies have shown that myeloid DC precursors are capable of suppressing T cell proliferation through a contact and nitric oxide (NO) -dependent mechanism. In addition, GM + IL-4, but not Flt3L, -derived DCs have been reported to suppress T cell proliferation by inducing T cell apoptosis. The SH2-containing inositol 5'-phosphatase (SHIP) is a potent suppressor of the PI3K pathway with known functions in regulating myeloid cell development and survival. However, little is known of SHIP's role in the suppressive ability of DC subsets. In this study we co-cultured polyclonally activated T cells with bone marrow derived DCs or DCs isolated from the spleens of WT and SHIP-/- mice to determine SHIP's role in DC-induced T cell suppression. We found that both WT and SHIP-deficient DCs derived with GM-CSF ± IL-4 profoundly suppress T cell proliferation while Flt3L-derived and splenic DCs do not. The mechanism of suppression proved to be contact dependent for WT and SHIP-deficient GM-CSF DCs. However, unlike WT, SHIP-deficient DCs do not produce detectable levels of NO. These results suggest a novel mechanism of myeloid DC-induced T cell suppression at work in SHIP-deficient DCs. This research is funded by an NCIC grant held by GK.
29
Cornelissen, Lenneke A. M., Kim C. M. Santegoets, Esther D. Kers-Rebel, Sandra A. J. F. H. Bossmann, Mark Ter Laan, Daniel Granado, and Gosse J. Adema. "Glioma-Associated Sialoglycans Drive the Immune Suppressive Phenotype and Function of Myeloid Cells." Pharmaceutics 16, no. 7 (July 19, 2024): 953. http://dx.doi.org/10.3390/pharmaceutics16070953.
Full textAbstract:
The tumor microenvironment of glioblastoma IDH-wildtype is highly immune suppressive and is characterized by a strong component of myeloid-derived suppressor cells (MDSCs). To interfere with the immune suppressive functions of MDSCs, a comprehensive understanding on how MDSCs acquire their suppressive phenotype is essential. Previously, we and others have shown a distinct Sialic acid-binding immunoglobulin-like lectin (Siglec) receptor expression profile for MDSCs in glioblastoma. Siglec receptors can transmit inhibitory signals comparable to PD-1 and are suggested to act as glyco-immune checkpoints. Here, we investigated how glioma specific Siglec-sialic acid interactions influence myeloid immune suppressive functions. Co-culturing monocytes with glioblastoma cells induced CD163 expression on the monocytes. Upon desialylation of the glioblastoma cells, this induction of CD163 was hampered, and furthermore, the monocytes were now able to secrete higher amounts of IL-6 and TNFα compared to fully sialylated glioblastoma cells. Additionally, Siglec-specific triggering using anti-Siglec-7 or Siglec-9 antibodies displayed a decreased TNFα secretion by the monocytes, validating the role of the Siglec–Sialic axis in the co-culture experiments. Together, our results demonstrate that glioblastoma cells induce a myeloid immune-suppressive phenotype that could be partly rescued by lowering the glioblastoma-associated sialic acid levels. This manuscript supports further research of the Siglec–Sialic acid axis in the context of glioblastoma and its potential to improve clinical outcome.
30
Rui, Ke, Jie Tian, Yue Hong, Liwei Lu, and Shengjun Wang. "Olfactory ecto-mesenchymal stem cells derived exosomes reverse the immunosuppressive capacity of myeloid-derived suppressor cells to ameliorates experimental Sjögren’s syndrome." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 238.11. http://dx.doi.org/10.4049/jimmunol.204.supp.238.11.
Full textAbstract:
Abstract Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by progressive inflammation and tissue damage of salivary glands and lacrimal glands. Our previous studies have shown myeloid-derived suppressor cells (MDSCs) were significantly increased but exhibited gradually diminished suppressive capacity in experimental Sjögren’s syndrome (ESS), thus leading to the development of the disease. In this study, we found that exosomes derived from olfactory ecto-mesenchymal stem cells (OE-MSCs-Exo) effectively enhanced the suppressive function of MDSCs on T cell proliferation, up-regulated MDSC-mediated suppressive factors (Arginase, ROS and NO), and subsequently suppressing the development of ESS. Additionally, levels of CD40, CD80, CD86 and MHCII on MDSCs were dramatically decreased, indicating the differentiated late stage MDSCs were reversed to the original undifferentiated status by OE-MSCs-Exo. Further investigation demonstrated that the increased suppressive function of MDSCs was orchestrated by IL-6, from both exosomes secreted IL-6 as well as its own IL-6 autocrine signaling pathway. Taken together, OE-MSCs-Exo have the potential to alleviate ESS severity through inducing MDSC expansion and potentiating their immunosuppressive function, indicating OE-MSCs-Exo may represent a new therapeutic strategy for the treatment of Sjögren’s syndrome and other autoimmune diseases.
31
Schroeder, Mark A., Julie Ritchey, Brian K. Dieckgraefe, and John F. DiPersio. "Pegylated Murine GM-CSF Increases Myeloid Derived Suppressor Cells In Vivo." Blood 118, no. 21 (November 18, 2011): 2967. http://dx.doi.org/10.1182/blood.v118.21.2967.2967.
Full textAbstract:
Abstract Abstract 2967 Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells initially identified in tumor bearing mice that have potent immunosuppressive capabilities. Recent evidence suggests that graft-versus-host disease (GvHD) can be abrogated by ex vivo expanded, bone marrow derived, MDSCs generated in the presence of GM-CSF, G-CSF and IL-13 (Highfill et al. Blood 2010 116 :5738). It remains to be shown whether phenotypic MDSCs identified in non-tumor bearing mice are capable of immune suppression. In addition, the mechanism by which an immature myeloid cell becomes a functional MDSC remains unknown. We hypothesized that pegylated murine GM-CSF (peg-mGM) may be protective from acute GvHD in MHC mismatched murine models by increasing regulatory T-cells (Treg) and MDSCs. Previously, we reported that peg-mGM increased circulating and splenic Tregs by 2–3 fold and they were functional in mixed leukocyte reactions (MLRs). We have also reported on the in vivo potential of mobilized splenocytes to abrogate murine GvHD. B6D2F1 mice receiving C57/Bl6 GM treated splenocytes had improved survival and less weight loss compared to G-CSF and PBS controls (3 independent experiments, n=15-19/group, GM vs. G p = 0.0005, GM vs. PBS p = 0.0005, G vs. PBS p = 0.5 (Log rank test)). In an attempt to identify cellular mediators of the reduced incidence of GvHD we investigated the impact of peg-mGM on putative MDSCs. We have observed an ∼8 fold increase in putative monocytic MDSCs (monoMDSCs) (CD11b+Ly6C+Ly6G-) and an ∼18 fold increase in putative granulocytic MDSCs (granMDSCs) (CD11b+Ly6C+Ly6G+) in the spleens and blood of mice mobilized with peg-mGM. To investigate the function of MDSCs we performed bead stimulated tritiated thymidine and CFSE based proliferation assays. We observed that granMDSCs and monoMDSCs isolated from spleens of mice treated with peg-mGM have potent suppressive function on bead stimulated T-cell proliferation exceeding that of na•ve Tregs at equal suppressor :Tcell ratios (Fold suppression of CD4+ T-cells: granMDSCs = 4.5, monoMDSCs = 2.3, Tregs = 1.08. Fold suppression of CD8+ T-cells: granMDSCs = 2.26, monoMDSCs = 1.4, Tregs = 1.05). To investigate mechanism we performed a transwell experiment using bead stimulated T-cells separated from MDSCs by a permeable membrane. Sorted monoMDSCs and granMDSCs were not suppressive in this assay suggesting the dependence on contact for inhibition of T-cell proliferation. In addition, we observed that in bead stimulated proliferation assays wells containing putative MDSCs had more dispersed beads suggesting possible sequestration of beads by the suppressor cells. To determine if all subsets were suppressive in an alternative non-bead based proliferation assay we coated plates with CD3/CD28 antibodies. Only the putative monoMDSCs were suppressive in this assay. We observed that suppression of bead stimulated T-cells was abrogated by adding an arginase-1 inhibitor, nor-NOHA, to cultures containing putative monoMDSCs. When attempting to validate these results in a MLR using MHC mismatched antigen-presenting cell (APC) stimulation, the suppressive effect was decreased or lost suggesting that the magnitude of stimulation by APC, bead or antibodies may affect activation and function of MDSCs; or, a critical factor produced in bead and antibody stimulated T-cell proliferation assays is lacking in the APC setting. We are currently functionally characterizing the monoMDSCs generated by treatment with peg-mGM and investigating potential secondary factors critical to the development of MDSCs such as IL-13 and IFN-gamma. In addition, future studies will evaluate the in vivo function of monoMDSCs generated by peg-mGM mobilization on GvHD and GVL outcomes. In summary, treatment with peg-mGM results in enrichment in functional MDSCs in the spleens of non-tumor bearing mice. The mechanism by which immature myeloid cells generated by peg-mGM become MDSCs is under investigation but appears to be contact dependent. This work is currently being translated in a clinical trial investigating the combination of GM-CSF and plerixafor for the mobilization of peripheral blood stem cells for allogeneic stem cell transplantation from matched sibling donors. Correlative studies to characterize stem cell subsets and evaluate the content of Tregs and MDSCs in the blood and apheresis product are ongoing. Disclosures: No relevant conflicts of interest to declare.
32
Vance, Jordan K., Travis W. Rawson, Jessica M. Povroznik, Kathleen M. Brundage, and Cory M. Robinson. "Myeloid-Derived Suppressor Cells Gain Suppressive Function during Neonatal Bacterial Sepsis." International Journal of Molecular Sciences 22, no. 13 (June 30, 2021): 7047. http://dx.doi.org/10.3390/ijms22137047.
Full textAbstract:
Neonates are at an increased risk of an infectious disease. This is consistent with an increased abundance of myeloid-derived suppressor cells (MDSCs) compared with older children and adults. Using a murine model of neonatal bacterial sepsis, we demonstrate that MDSCs modulate their activity during an infection to enhance immune suppressive functions. A gene expression analysis shows that MDSCs increased NOS2, Arg-1 and IL-27p28 expression in vitro and in vivo in response to Escherichia coli O1:K1:H7 and this is regulated at the level of the gene expression. Changes in the effector gene expression are consistent with increased enzymatic activity and cytokine secretion. The neonatal MDSCs express toll-like receptor (TLR) 2, 4 and 5 capable of recognizing pathogen-associated molecular patterns (PAMPS) on E. coli. However, a variable level of effector expression was achieved in response to LPS, peptidoglycan or flagellin. Individual bacterial PAMPs did not stimulate the expression of Arg-l and IL-27p28 equivalently to E. coli. However, the upregulation of NOS2 was achieved in response to LPS, peptidoglycan and flagella. The increased immune suppressive profile translated to an enhanced suppression of CD4+ T cell proliferation. Collectively, these findings increase our understanding of the dynamic nature of MDSC activity and suggest that these cells abundant in early life can acquire activity during an infection that suppresses protective immunity.
33
Shen, Li, and Roberto Pili. "Tasquinimod targets suppressive myeloid cells in the tumor microenvironment." OncoImmunology 8, no. 10 (May 7, 2018): e1072672. http://dx.doi.org/10.1080/2162402x.2015.1072672.
Full text
34
Kumar, Vishnupriyan, Michael A. Giacomantonio, and Shashi Gujar. "Role of Myeloid Cells in Oncolytic Reovirus-Based Cancer Therapy." Viruses 13, no. 4 (April 10, 2021): 654. http://dx.doi.org/10.3390/v13040654.
Full textAbstract:
Oncolytic reovirus preferentially targets and kills cancer cells via the process of oncolysis, and additionally drives clinically favorable antitumor T cell responses that form protective immunological memory against cancer relapse. This two-prong attack by reovirus on cancers constitutes the foundation of its use as an anticancer oncolytic agent. Unfortunately, the efficacy of these reovirus-driven antitumor effects is influenced by the highly suppressive tumor microenvironment (TME). In particular, the myeloid cell populations (e.g., myeloid-derived suppressive cells and tumor-associated macrophages) of highly immunosuppressive capacities within the TME not only affect oncolysis but also actively impair the functioning of reovirus-driven antitumor T cell immunity. Thus, myeloid cells within the TME play a critical role during the virotherapy, which, if properly understood, can identify novel therapeutic combination strategies potentiating the therapeutic efficacy of reovirus-based cancer therapy.
35
Abdelfattah, Nourhan, Parveen Kumar, Caiyi Wang, Jia-Shiun Leu, David Baskin, William Flynn, Ruli Gao, et al. "Abstract 5871: Pan-cancer myeloid cell analysis at the single cell level reveals the influence of distinct organ sites in myeloid cell phenotypes and support targeting S100A4 to reverse immune suppression." Cancer Research 83, no. 7_Supplement (April 4, 2023): 5871. http://dx.doi.org/10.1158/1538-7445.am2023-5871.
Full textAbstract:
Abstract With abundant pro-tumorigenic myeloid cells and few tumoricidal tumor-infiltrating lymphocytes (<5%), GBM is representative of “immune cold” tumors. As such, many different types of immunotherapies have failed to show significant benefits for most glioma patients. Hence, a better understanding of drivers of the immune suppressive microenvironment in GBM and other immune cold tumors is urgently needed to guide future immunotherapy development and application. We recently analyzed 201,986 human glioma and immune cells from 44 tissue fragments from 18 human glioma patients, and present a comprehensive and high-resolution cellular, molecular, and spatial heterogeneity atlas of human glioma. We report an extensive spatial and molecular heterogeneity of glioma and immune cells within the same patient. In addition, we discovered that cell:cell communication between glioma:myeloid cells is considerably more robust than glioma:T-cells, indicating that myeloid cells form a communication hub in vivo. To gain a deeper understanding of these important immune cells, we analyzed 83,479 glioma-infiltrating myeloid cells and identified 9 molecularly distinct myeloid subtypes: 3 microglia subtypes, 3 bone marrow-derived macrophage (BMDM) subtypes, MDSCs, neutrophils, and dendritic cells. Notably, we found that five of these myeloid cell subtype gene signatures are significant predictors of glioma patient survival, independent of glioma cell mutational profiles or gene expression patterns. Leveraging our dataset, we also identified a novel immunotherapy target that is highly expressed in immune-suppressive macrophages and T cells but not in anti-tumor leukocytes: S100A4. We provide both in vitro and in vivo evidence that S100a4 deletion in stromal cells is sufficient to reprogram the immune microenvironment and significantly extend the survival of two independent glioma models. To broaden the potential impact of targeting S100A4 as a selective modulator of immune suppressive leukocytes, we compared the molecular signatures of glioma-associated myeloid cells to those from 12 other cancer types and peripheral blood myeloid cells. We found that S100A4 expression pattern is highly consistent among all tumor types, where its expression is highest in the monocytes and MDSCs and low in most DCs and tissue-resident macrophages. Our preliminary analysis also shows that myeloid cells in gliomas are molecularly distinct from corresponding cell types in other cancers, strongly indicating the role brain microenvironment in influencing the infiltrating BMDM maturation and polarization. Citation Format: Nourhan Abdelfattah, Parveen Kumar, Caiyi Wang, Jia-Shiun Leu, David Baskin, William Flynn, Ruli Gao, Kumar Pichumani, Omkar Ijare, Stephanie Wood, Suzanne Powell, David Haviland, Brittany Parker Kerrigan, Frederick Lang, Sujit Prabhu, Kristin Huntoon, Wen Jiang, Betty Kim, Joshy George, Kyuson Yun. Pan-cancer myeloid cell analysis at the single cell level reveals the influence of distinct organ sites in myeloid cell phenotypes and support targeting S100A4 to reverse immune suppression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5871.
36
Anderson, Hannah, Gregory P. Takacs, Christian Kreiger, Defang Luo, Libin Rong, Jeffrey K. Harrison, and Tracy Stepien. "209 A CTS Team Approach to Modeling Migration and Suppression of CCR2+/CX3CR1+ Myeloid Cells in Glioblastoma." Journal of Clinical and Translational Science 6, s1 (April 2022): 32. http://dx.doi.org/10.1017/cts.2022.111.
Full textAbstract:
OBJECTIVES/GOALS: Evaluate the migration and immune suppressive functions of CCR2+/CX3CR1+ myeloid-derived suppressor cells (MDSCs). Integrate experimental data and biologically relevant mathematical models of infiltrating MDSCs in the context of glioblastoma (GBM). METHODS/STUDY POPULATION: CCR2+/CX3CR1+ cells were enriched from bone marrow obtained from CCR2(+/RFP)/CX3CR1(+/GFP) glioma-bearing mice to evaluate their immune-suppressive phenotype and ability to migrate to CCL2 and CCL7. Fluorescent imaging and quantification were performed on a range of tumor sizes to acquire vasculature, tumor, T cell, and MDSC densities. A system of ordinary differential equations was constructed to represent the temporal dynamics of glioma cells, T cells, and MDSCs within the tumor microenvironment. The Approximate Bayesian Computation method was used to determine probability distributions of important parameters, such as the suppression rate of T cells by MDSCs. RESULTS/ANTICIPATED RESULTS: CCR2+/CX3CR1+ M-MDSCs isolated from the bone marrow of tumor-bearing mice suppress CD8+ T cell proliferation and IFNγ production. CCR2+/CX3CR1+ cells migrate to recombinant and KR158B glioma sourced CCL2 and CCL7. Parameter values determined by the Approximate Bayesian Computation method agreed with parameter values from experimental data. This result further validated the structure and results of the mathematical model when performing computer simulations; thus, we can predict CCR2+/CX3CR1+ M-MDSC infiltration over time. DISCUSSION/SIGNIFICANCE: The immune-suppressive microenvironment in GBM contributes to poor outcomes despite standard of care. This study integrates biological and mathematical models to better understand infiltrating immune-suppressive cells, namely CCR2+/CX3CR1+ M-MDSCs. Future directions include modeling immunotherapies.
37
Peñaloza, Hernán F., Janet S. Lee, and Prabir Ray. "Neutrophils and lymphopenia, an unknown axis in severe COVID-19 disease." PLOS Pathogens 17, no. 9 (September 2, 2021): e1009850. http://dx.doi.org/10.1371/journal.ppat.1009850.
Full textAbstract:
The Coronavirus Disease 2019 (COVID-19) is caused by the betacoronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus that can mediate asymptomatic or fatal infections characterized by pneumonia, acute respiratory distress syndrome (ARDS), and multi-organ failure. Several studies have highlighted the importance of B and T lymphocytes, given that neutralizing antibodies and T cell responses are required for an effective immunity. In addition, other reports have described myeloid cells such as macrophages and monocytes play a major role in the immunity against SARS-CoV-2 as well as dysregulated pro-inflammatory signature that characterizes severe COVID-19. During COVID-19, neutrophils have been defined as a heterogeneous group of cells, functionally linked to severe inflammation and thrombosis triggered by degranulation and NETosis, but also to suppressive phenotypes. The physiological role of suppressive neutrophils during COVID-19 and their implications in severe disease have been poorly studied and is not well understood. Here, we discuss the current evidence regarding the role of neutrophils with suppressive properties such as granulocytic myeloid-derived suppressor cells (G-MDSCs) and their possible role in suppressing CD4+ and CD8+ T lymphocytes expansion and giving rise to lymphopenia in severe COVID-19 infection.
38
Parker, Katherine, and Suzanne Ostrand-Osenberg. "Title: HMGB1 both enhances and blocks myeloid-derived suppressor cell potency Katherine H. Parker, Suzanne Ostrand-Rosenberg Department of Biological Sciences, University of Maryland Baltimore County, Baltimore MD 21250 (162.40)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 162.40. http://dx.doi.org/10.4049/jimmunol.188.supp.162.40.
Full textAbstract:
Abstract Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells that accumulate in individuals with cancer and inflammation and play a pivotal role in tumor immunity by suppressing T-cell activation and secreting proinflammatory molecules. MDSC potency is mediated by immune suppressive factors such as inducible NO synthase (iNOs), arginase, and reactive oxygen species (ROS). MDSC also impair tumor immunity through crosstalk with macrophages in which IL-10 production increases while IL-12 production decreases, causing a shift in innate and adaptive immunity towards a type 2 tumor-promoting phenotype. Nuclear protein, High Mobility Group Box1 (HMGB1) is the second most abundant protein within a cell and is released from myeloid cells as a danger response to sepsis, infection, or arthritis. It’s release promotes inflammatory responses. HMGB1 signals through a multitude of receptors including TLR4 and RAGE, which are expressed by MDSC. In contrast to other inflammatory mediators which increase MDSC potency, HMGB1 reduced the suppressive mechanisms of TLR4-\- and wildtype MDSC, by reducing ROS in TLR4-\- MDSC and iNOs levels in wildtype MDSC. Glycyrrhizin, an HMGB1 inhibitor, decreased IL-10 in co-cultures of macrophages and MDSC. These findings suggest that HMGB1 plays both anti- and pro-inflammatory roles in regulating MDSC suppressive activity.
39
Ding, Xinchun, Lingyan Wu, Cong Yan, and Hong Du. "Establishment of lal-/- Myeloid Lineage Cell Line That Resembles Myeloid-Derived Suppressive Cells." PLOS ONE 10, no. 3 (March 25, 2015): e0121001. http://dx.doi.org/10.1371/journal.pone.0121001.
Full text
40
Wang, Xiang-Yang, Huanfa Yi, Chunqing Guo, and Xiaofei Yu. "Myeloid-derived suppressive cells enhance differentiation of Th17 cells in an IL-1β dependent manner (P1096)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 185.22. http://dx.doi.org/10.4049/jimmunol.190.supp.185.22.
Full textAbstract:
Abstract Myeloid-derived suppressive cells (MDSCs) have been implicated in the pathogenesis of several diseases, including cancer and autoimmune disorders. We found that CD11b+Gr-1+ MDSCs from tumor- or experimental autoimmune encephalomyelitis (EAE)-bearing mice promote the differentiation of naïve CD4+ T cell precursors into Th17 cells in a highly efficient manner. The presence of MDSCs also results in elevation of IL-17A production and upregulation of the orphan nuclear receptor RORA and RORC in T cells. IL-1β-derived from MDSCs is identified as a major mediator of the enhanced Th17 differentiation, which involves the IL-1 receptor on CD4+ T cells. Depletion of MDSCs leads to significantly reduced Th17 response and decreased clinical scores of EAE as well as myelin injury. Our data reveal a new feature of MDSC action in the shaping of inflammatory Th17 cell responses and provide additional insights into the pleiotropic functions of this myeloid cell population. These new findings support the concept of targeting MDSCs for potentially effective intervention of Th17 cell/IL-17-mediated immunopathology in cancer and autoimmune diseases (e.g., multiple sclerosis).
41
Hou, Yu, Qi Feng, Miao Xu, Guo-sheng Li, Xue-na Liu, Zi Sheng, Hai Zhou, et al. "High-dose dexamethasone corrects impaired myeloid-derived suppressor cell function via Ets1 in immune thrombocytopenia." Blood 127, no. 12 (March 24, 2016): 1587–97. http://dx.doi.org/10.1182/blood-2015-10-674531.
Full textAbstract:
Key Points The impaired suppressive function of myeloid-derived suppressor cells plays a role in the pathogenesis of immune thrombocytopenia. The effect of dexamethasone in correcting dysfunction of myeloid-derived suppressor cells suggests a new therapeutic mechanism of high-dose dexamethasone in patients with immune thrombocytopenia.
42
Miner, Samantha, Sawa Ito, Kazushi Tanimoto, Nancy F. Hensel, Fariba Chinian, Keyvan Keyvanfar, Christopher S. Hourigan, et al. "Myeloid Leukemias Directly Suppress T Cell Proliferation Through STAT3 and Arginase Pathways." Blood 122, no. 21 (November 15, 2013): 3885. http://dx.doi.org/10.1182/blood.v122.21.3885.3885.
Full textAbstract:
Abstract The immune-editing effect of myeloid leukemia has recently been reported in several studies. We previously demonstrated that the K562 leukemia-derived cell line suppresses T cell proliferation, which suggests that myeloid leukemia may function in a similar way to myeloid derived suppressor cells (MDSC). While the mechanism of suppression in leukemia is not fully understood, recent murine and human studies suggest that the STAT3 and arginase pathways play a key role in the immunosuppressive function of MDSC. We hypothesized that myeloid leukemia utilizes the MDSC STAT3 and arginase pathway to evade immune control, and block anti-leukemic immune responses. To evaluate the suppressive capacity of myeloid leukemia on T cell proliferation, we isolated CD34+ blasts and myeloid derived suppressor cells (MDSC: CD11b+CD14+) from blood of primary leukemia samples by FACS sorting (n=5). These cells were co-cultured with CFSE-labeled CD4+ T cells (n=9), previously isolated from healthy donor PBMCs using an automated cell separator (RoboSep). After stimulating with CD3/CD28 Dynabeads (Invitrogen, New York, USA) for 72 hours, proliferation was measured by CFSE dilution of the viable cell population. In three myeloid leukemias studied, CD4+ T cell proliferation was significantly suppressed in the presence of primary CD34 blasts and MDSC cells (p<0.001). Interestingly, CD34 blasts demonstrated a greater suppressive effect on T cells compared to MDSC cells for these samples (not statistically significant p=0.61). Next we repeated the proliferation assay using five leukemia cell lines: THP-1 and AML1 (derived from AML), K562 and CML1 (derived from CML), and the Daudi lymphoid-derived leukemia cell line. After staining with cell tracer dye and irradiating 100Gy, the cells were co-incubated with CFSE-labeled CD4+ T cells from healthy volunteers (n=6). We found that CD4+ T cell proliferation in the presence of the myeloid leukemia cell lines was significantly suppressed (mean proliferation 5.7±0.9% to 26.1±10.7%: p<0.0001 to 0.05) compared to lymphoid cell lines (mean proliferation 76.3±8.2%: p>0.05), consistent with the results obtained with the primary leukemia samples. To evaluate the impact of STAT3 and arginase on the immunosuppressive function of myeloid leukemia, the five cell lines were primed overnight with either arginase inhibitor (N(ω)-Hydroxy-nor-L-arginine; EMD Biosciences, Inc., California, USA) or two STAT3 inhibitors (STAT3 Inhibitor VI or Cucurbitacin I; EMD Millipore, Massachusetts, USA). Then, CD4+ T cells from healthy donors (n=3) were cultured with either (1) leukemia without any inhibitor (2) leukemia in the presence of inhibitor (3) leukemia primed with inhibitor. Priming leukemia with arginase inhibitor and STAT3 inhibitors almost completely abrogated their suppressive effect of T cell proliferation (p<0.001). We conclude that myeloid leukemia, like MDSC, directly immunosuppresses T cells, through STAT-3 and arginase. This finding may underlie the immune-editing of T cells by myeloid leukemia. Our results suggest that STAT3 inhibitors could be used to augment leukemia-targeted immunotherapy. Further investigation of T cell biology within the leukemia microenvironment is needed to further define immune editing mechanisms in myeloid leukemia. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures: No relevant conflicts of interest to declare.
43
Griesinger, Andrea, Eric Prince, Andrew Donson, Kent Riemondy, Timothy Ritzman, Faith Harris, Vladimir Amani, et al. "EPEN-22. SINGLE-CELL RNA SEQUENCING IDENTIFIES UPREGULATION OF IKZF1 IN PFA2 MYELOID SUBPOPULATION DRIVING AN ANTI-TUMOR PHENOTYPE." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii312. http://dx.doi.org/10.1093/neuonc/noaa222.159.
Full textAbstract:
Abstract We have previously shown immune gene phenotype variations between posterior fossa ependymoma subgroups. PFA1 tumors chronically secrete IL-6, which pushes the infiltrating myeloid cells to an immune suppressive function. In contrast, PFA2 tumors have a more immune activated phenotype and have a better prognosis. The objective of this study was to use single-cell(sc) RNAseq to descriptively characterize the infiltrating myeloid cells. We analyzed approximately 8500 cells from 21 PFA patient samples and used advanced machine learning techniques to identify distinct myeloid and lymphoid subpopulations. The myeloid compartment was difficult to interrupt as the data shows a continuum of gene expression profiles exist within PFA1 and PFA2. Through lineage tracing, we were able to tease out that PFA2 myeloid cells expressed more genes associated with an anti-viral response (MHC II, TNF-a, interferon-gamma signaling); while PFA1 myeloid cells had genes associated with an immune suppressive phenotype (angiogenesis, wound healing, IL-10). Specifically, we found expression of IKZF1 was upregulated in PFA2 myeloid cells. IKZF1 regulates differentiation of myeloid cells toward M1 or M2 phenotype through upregulation of either IRF5 or IRF4 respectively. IRF5 expression correlated with IKZF1, being predominately expressed in the PFA2 myeloid cell subset. IKZF1 is also involved in T-cell activation. While we have not completed our characterization of the T-cell subpopulation, we did find significantly more T-cell infiltration in PFA2 than PFA1. Moving forward these studies will provide us with valuable information regarding the molecular switches involved in the tumor-immune microenvironment and to better develop immunotherapy for PFA ependymoma.
44
Yao, G., S. Wang, and L. Sun. "THU0226 MESENCHYMAL STEM CELL TRANSPLANTATION AMELIORATES EXPERIMENTAL SJÖGREN’S SYNDROME BY DOWNREGUALTING MDSCS VIA COX2/PGE2 PATHWAY." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 340.1–340. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1391.
Full textAbstract:
Background:Although mesenchymal stem cells (MSCs) transplantation have been demonstrated to be an effective therapeutic approach to treat experimental Sjögren’s syndrome (ESS)1, the specific underlying mechanisms remain to be elucidated. Myeloid-derived suppressor cells (MDSCs) were significantly increased with decreased suppressive capacity during disease development in ESS2-3. However, the therapeutic effects and mechanisms by which MSCs regulating MDSCs in SS still remain unknown.Objectives:Here we aim to explore whether regulation of MDSCs was responsible for the beneficial effects of MSC transplantation on SS.Methods:The MSCs were infused intonon-obese diabetic (NOD) mice via the tail vein. The histological features of submandibular glands, lung, saliva flow rate were evaluated. The number and immune-suppressive activity of MDSCs, the subsets of MDSCs, polymorphonuclear MDSCs (PMN-MDSCs) and monocytic-MDSCs (M-MDSCs) in NOD mice were determined. The bone marrow cells under MDSCs differentiation conditions were co-cultured with or without MSCs. The COX2 inhibitor NS-398, anti-TGF-β1, or anti-IFN-β antibodies were added to coculture medium of MSCs and MDSCs induced from bone marrow cells respectively.Results:We found that MDSCs in bone marrow and peripheral blood increased in ESS mice. MSC transplantation ameliorated SS-like syndrome and down-regulated the percentages of MDSCs, PMN-MDSCs and M-MDSCs and promoted their suppressive ability in ESS mice significantly (Figure 1). In vitro, MSCs could down-regulate the differentiation and up-regulate the suppressive ability of MDSCs. Mechanistically, MSCs inhibited the differentiation of MDSCs and PMN-MDSCs via secreting prostaglandin E2, and inhibited the differentiation of M-MDSCs by secreting interferon-β (Figure 2).Figure 1.MSCs ameliorated SS symptoms and decreased MDSCs in NOD mice.Figure 2.MSCs inhibited the differentiation of PMN-MDSCs and M-MDSCs by COX2/PGE2 and IFN-β respectively.Conclusion:Our findings suggested that MSCs alleviated SS-like symptoms by suppressing the aberrant accumulation and improving the suppressive function of MDSCs in ESS mice via COX2/PGE2 pathway.References:[1]Shi B, Qi J, Yao G, et al. Mesenchymal stem cell transplantation ameliorates Sjögren’s syndrome via suppressing IL-12 production by dendritic cells. Stem Cell Res Ther, 2018; 9(1):308.[2]Qi J, Li D, Shi G, et al. Myeloid-derived suppressor cells exacerbates Sjögren’s syndrome by inhibiting Th2 immune responses. Mol Immunol, 2018; 101:251-258.[3]Tian J, Rui K, Hong Y, et al. Increased GITRL impairs the function of myeloid-derived suppressor cells and exacerbates primary Sjögren’s syndrome. J Immunol, 2019; 202(6):1693-1703.Disclosure of Interests:None declared
45
Solito, Samantha, Erika Falisi, Claudia Marcela Diaz-Montero, Andrea Doni, Laura Pinton, Antonio Rosato, Samuela Francescato, et al. "A human promyelocytic-like population is responsible for the immune suppression mediated by myeloid-derived suppressor cells." Blood 118, no. 8 (August 25, 2011): 2254–65. http://dx.doi.org/10.1182/blood-2010-12-325753.
Full textAbstract:
Abstract We recently demonstrated that human BM cells can be treated in vitro with defined growth factors to induce the rapid generation of myeloid-derived suppressor cells (MDSCs), hereafter defined as BM-MDSCs. Indeed, combination of G-CSF + GM-CSF led to the development of a heterogeneous mixture of immature myeloid cells ranging from myeloblasts to band cells that were able to suppress alloantigen- and mitogen-stimulated T lymphocytes. Here, we further investigate the mechanism of suppression and define the cell subset that is fully responsible for BM-MDSC–mediated immune suppression. This population, which displays the structure and markers of promyelocytes, is however distinct from physiologic promyelocytes that, instead, are devoid of immuosuppressive function. In addition, we demonstrate that promyelocyte-like cells proliferate in the presence of activated lymphocytes and that, when these cells exert suppressive activity, they do not differentiate but rather maintain their immature phenotype. Finally, we show that promyelocyte-like BM-MDSCs are equivalent to MDSCs present in the blood of patients with breast cancer and patients with colorectal cancer and that increased circulating levels of these immunosuppressive myeloid cells correlate with worse prognosis and radiographic progression.
46
Ohayon, David E., Taylor R. Brooks, Sarah E. Mahl, Stacey A. Cranert, and Stephen N. Waggoner. "Natural killer cells support myeloid suppressor cell expansion during persistent viral infection." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 78.36. http://dx.doi.org/10.4049/jimmunol.198.supp.78.36.
Full textAbstract:
Abstract Persistent viral infections in mice (e.g. lymphocytic choriomeningitis virus, LCMV) and humans (e.g. HIV, hepatitis C virus) are characterized by chronic inflammation. This sustained inflammatory milieu promotes T cell exhaustion, which limits harmful tissue damage but prevents effective viral control. We found that natural killer (NK) cells aid in the establishment of this tolerogenic state through cytolytic elimination of antiviral T cells. In parallel, others shown that chronic infection encourages expansion of immunoregulatory IL-10-expressing myeloid cells and bona fide myeloid-derived suppressor cells (MDSCs) that contribute to T cell inhibition immune exhaustion and cell injury. We now report that depletion of NK cells prior to persistent infection with the clone 13 strain of LCMV abrogates the expansion of immunosuppressive myeloid cells. In the absence of NK cells, the levels of myelo-stimulatory cytokines, including TNF-a, MCP-1, and IL-6 were also reduced. Furthermore, frequencies of myeloid precursor cells were reduced in the bone marrow during infection in the absence of NK cells. Our results suggest that NK cells support an inflammatory milieu promoting expansion of the myeloid niche and specifically suppressive myeloid cells during chronic infection. This cross-talk between NK cells and myeloid cells during inflammation has the potential to contribute to immune dysfunction during both chronic infection and in cancer.
47
Vakana, Eliza, Jessica K. Altman, Heather Glaser, Nicholas J. Donato, and Leonidas C. Platanias. "Antileukemic effects of AMPK activators on BCR-ABL–expressing cells." Blood 118, no. 24 (December 8, 2011): 6399–402. http://dx.doi.org/10.1182/blood-2011-01-332783.
Full textAbstract:
Abstract The mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in growth and survival of BCR-ABL transformed cells. AMPK kinase is a metabolic sensor that exhibits suppressive effects on the mTOR pathway and negatively regulates mTOR activity. We report that AMPK activators, such as metformin and 5-aminoimidazole-4-carboxamide ribonucleotide, suppress activation of the mTOR pathway in BCR-ABL–expressing cells. Treatment with these inhibitors results in potent suppression of chronic myeloid leukemia leukemic precursors and Ph+ acute lymphoblastic leukemia cells, including cells expressing the T315I-BCR-ABL mutation. Altogether, our data suggest that AMPK is an attractive target for the treatment of BCR-ABL–expressing malignancies and raise the potential for use of AMPK activators in the treatment of refractory chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia.
48
Peretz, Tsuri, Yoav Pizem, Liat Iancovici, Ella Peled, Motti Hakim, Sharon Hashmueli, Ilana Mandel, Yair Sapir, and Tehila Ben Moshe. "Abstract 3920: BND-35, a novel anti-ILT3 antibody for remodulation of the tumor microenvironment." Cancer Research 84, no. 6_Supplement (March 22, 2024): 3920. http://dx.doi.org/10.1158/1538-7445.am2024-3920.
Full textAbstract:
Abstract Background: ILT3 (LILRB4) is expressed in various suppressive myeloid cells including tumor associated macrophages (TAM), myeloid derived suppressor cells (MDSCs) and tolerogenic dendritic cells (DCtol). The binding of ILT3 to its ligands induces an immunosuppressive phenotype in myeloid cells, mediates the inhibition of T cells activity and generates an immunosuppressive tumor microenvironment (TME) which supports tumor growth. The inhibition of ILT3 can restore the anti-tumor activity of myeloid cells and T cells, and thus remodulate the TME from immunosuppressive to pro-inflammatory. Here we describe preclinical characterization of BND-35, a humanized IgG4, ILT3 antagonist antibody developed for the treatment of solid tumors. Methods: BND-35 binding to ILT3 was evaluated by flow cytometry, ELISA and surface plasmon resonance. We investigated the ability of BND-35 to block ILT3 interactions with APOE and fibronectin, to enhance the pro inflammatory activity of various myeloid cells and reverse ILT3-mediated immune suppression of T cells by different suppressive myeloid cells using ELISA and in vitro and ex vivo cell-based assays. The anti-tumor activity of BND-35 was also evaluated in vivo in hILT3 transgenic mouse tumor models as well as in tumoroid systems generated from cancer patients. Results: BND-35 binds ILT3, but not other ILT-family receptors, with low nanomolar affinity and blocks its interaction with APOE and fibronectin in a concentration-dependent manner. ILT3 blockade with BND-35 restored the pro-inflammatory activity of FcR-stimulated DCs and THP1 cells inhibited by fibronectin. BND-35 was also shown to restore an M1 phenotype in cancer patients’ derived monocytes differentiated in the presence of autologous tumor cells. In addition, BND-35 restored T cell activity (both, CD4 and CD8 T cells) inhibited by either DCtol, MDSCs or M2 cells as a single agent and in combination with anti PD-1. BND-35 enhanced immune activity in a unique system of patient-derived tumoroids as evidenced by the secretion of pro-inflammatory cytokines. In vivo, blocking ILT3 activity with BND-35 resulted in decreased tumor growth and induced a pro-inflammatory phenotype in tumor resident T cells and myeloid cells populations as a single agent and in combination with anti PD-1. Conclusions: BND-35 is an anti-ILT3 antagonist antibody that was shown to induce potent pro inflammatory activity of myeloid cells and enhance T cells activity inhibited by ILT3 expressing myeloid suppressive cells in multiple in vitro, ex vivo and in vivo models. By doing so, BND-35 can lead to TME remodelling from immunosuppressive to proinflammatory. Safety, tolerability, and anti-tumor activity of BND-35 will be explored in a first-in-human clinical trial in cancer patients with solid tumors. Citation Format: Tsuri Peretz, Yoav Pizem, Liat Iancovici, Ella Peled, Motti Hakim, Sharon Hashmueli, Ilana Mandel, Yair Sapir, Tehila Ben Moshe. BND-35, a novel anti-ILT3 antibody for remodulation of the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3920.
49
Good, Logan, Brooke Benner, and William E. Carson. "Bruton’s tyrosine kinase: an emerging targeted therapy in myeloid cells within the tumor microenvironment." Cancer Immunology, Immunotherapy 70, no. 9 (April 5, 2021): 2439–51. http://dx.doi.org/10.1007/s00262-021-02908-5.
Full textAbstract:
AbstractBruton’s tyrosine kinase (BTK) is a non-receptor kinase belonging to the Tec family of kinases. The role of BTK in B cell receptor signaling is well defined and is known to play a key role in the proliferation and survival of malignant B cells. Moreover, BTK has been found to be expressed in cells of the myeloid lineage. BTK has been shown to contribute to a variety of cellular pathways in myeloid cells including signaling in the NLRP3 inflammasome, receptor activation of nuclear factor-κβ and inflammation, chemokine receptor activation affecting migration, and phagocytosis. Myeloid cells are crucial components of the tumor microenvironment and suppressive myeloid cells contribute to cancer progression, highlighting a potential role for BTK inhibition in the treatment of malignancy. The increased interest in BTK inhibition in cancer has resulted in many preclinical studies that are testing the efficacy of using single-agent BTK inhibitors. Moreover, the ability of tumor cells to develop resistance to single-agent checkpoint inhibitors has resulted in clinical studies utilizing BTK inhibitors in combination with these agents to improve clinical responses. Furthermore, BTK regulates the immune response in microbial and viral infections through B cells and myeloid cells such as monocytes and macrophages. In this review, we describe the role that BTK plays in supporting suppressive myeloid cells, including myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM), while also discussing the anticancer effects of BTK inhibition and briefly describe the role of BTK signaling and BTK inhibition in microbial and viral infections.
50
Griesinger, Andrea, Kent Riemondy, Andrew Donson, Nicholas Willard, Eric Prince, Faith Harris, Vladimir Amani, et al. "EPEN-07. SINGLE-CELL RNA SEQUENCING IDENTIFIES A UNIQUE MYELOID SUBPOPULATION ASSOCIATED WITH MESENCHYMAL TUMOR SUBPOPULATION IN POOR OUTCOME PEDIATRIC EPENDYMOMA." Neuro-Oncology 23, Supplement_1 (June 1, 2021): i14—i15. http://dx.doi.org/10.1093/neuonc/noab090.057.
Full textAbstract:
Abstract We have previously shown immune gene phenotype variations between posterior fossa ependymoma subgroups. PFA1 tumors chronically secrete IL-6, which induces secretion of myeloid cell IL-8 and pushes the infiltrating myeloid cells to an immune suppressive function. In contrast, PFA2 tumors have a more immune activated phenotype associated with a better prognosis. The objective of this study was to use single-cell(sc) RNAseq to descriptively characterize the infiltrating myeloid cells. We analyzed approximately 8500 cells from 21 PFA patient samples. Using advanced machine learning, we identified eight myeloid cell subpopulations with unique gene expression profiles. Interestingly, only one subpopulation was significantly enriched in PFA1 tumors. This subpopulation, denoted as the hypoxia myeloid subpopulation, was defined by genes associated with angiogenesis, response to hypoxia, wound healing, cell migration, neutrophil activation and response to oxygen levels. These myeloid cells also share similar gene expression profile to a mesenchymal tumor subpopulation (MEC) enriched in PFA1 and associated with poor outcome in EPN patients. This tumor subpopulation was the only population expressing IL-6. Using immunohistochemistry, we found the hypoxia myeloid located in regions of tumor necrosis and perivascular niches. The MEC cells were also more abundant in these regions. In an independent single-cell cytokine release assay, we identified eight subpopulations of functional myeloid cells. One subpopulation significantly secreted IL-8, which represented the hypoxia subpopulation based on IL-8 gene expression in the scRNAseq dataset. This data suggests the tumor necrosis resulting in the development of MEC tumor subpopulation is driving the immune suppressive myeloid phenotype in PFA1 tumors through polarization of myeloid cells to the hypoxia subpopulation. Further studies are needed to determine how these myeloid cells interact with the lymphocyte subpopulations and whether they contribute to the progression of PFA1 EPN.