Effects of in vitro ATRA treatment on human MDSC expansion and function.

125 Background: Myeloid derived suppressor cells (MDSCs) are a heterogeneous population of immature immunosuppressive myeloid cells that are expanded in tumor bearing hosts. Melanoma patients with high frequencies of MDSCs have decreased overall survival and an increased risk of death and disease progression, as well as impaired responses to ipilimumab. Targeting MDSCs to decease their frequency or suppressive activity may provide an effective means to improve the efficacy of anti-cancer therapies. All-trans retinoic acid (ATRA) is a vitamin A derivative currently used to treat APL that may target MDSCs. ATRA differentiates immature myeloid cells into macrophages, dendritic cells, or granulocytes. ATRA has been tested as an MDSC targeting agent in two completed caner clinical trials and is being investigated in several other open and completed trials. Methods: We purified myeloid cells from LRS chambers collected from normal donors. The purified cells were treated with GM-CSF+IL-6, GM-CSF+IL-4, or melanoma conditioned media with or without ATRA. After 5 days of incubation, PCR was used to determine the expression of immunoregulatory genes. Additionally, we used a MLR to determine the effect of ATRA on MDSC’s T cell suppressive function. Results: Here we report that in vitro ATRA treatment decreases the expression of ARG1, NOX1, INOS, and PD-L1. Further, we report that ATRA treatment improved T cell proliferation. Conclusions: Controlling MDSC suppressive function and accumulation may provide a mechanism to improve the efficacy of many current cancer therapies. Here we show that ATRA reduces the expression of the immunosuppressive genes ARG1, NOX1, INOS, and PD-L1 in MDSCs. Additionally, we show that treatment of MDSCs with ATRA decreases MDSC’s ability to suppress T cell proliferation. These results indicate that ATRA may improve the efficacy of conventional and immnunotherapeutic treatments.

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Myeloid Suppressive Cells Mobilized by GM-CSF in Non-Tumor Bearing Mice Are Dependent On Interferon Gamma for Function

Blood ◽

10.1182/blood.v120.21.832.832 ◽

2012 ◽

Vol 120 (21) ◽

pp. 832-832

Author(s):

Mark A. Schroeder ◽

Julie Ritchey ◽

John F. DiPersio

Keyword(s):

Bone Marrow ◽

Cell Proliferation ◽

T Cells ◽

T Cell ◽

T Cell Proliferation ◽

Suppressive Function ◽

Gm Csf ◽

Tumor Bearing

Abstract Abstract 832 Myeloid-derived-suppressor cells (MDSCs) are enriched in tumors, and exist to a lesser extent in the blood, spleen and bone marrow of tumor bearing mice. Monocytic MDSCs (monoMDSCs) suppress CD8+ T-cells via expression of Arginase 1 (ARG1) and inducible nitric oxide synthase (iNOS). Tumor derived factors are critical to the maintenance of MDSCs and preventing differentiation to mature macrophages and dendritic cells. GM-CSF is a hematopoietic cytokine that can be secreted by tumors and promotes MDSC generation. Cells phenotypically similar to MDSCs can be isolated from blood of normal individuals but lack suppressive function. Hematopoietic peripheral blood stem cell mobilization with G-CSF and GM-CSF enriches for cells phenotypically similar to MDSCs. There is limited data on the role and function of these cells isolated from non-tumor bearing, normal individuals. Recent evidence suggests that graft-versus-host disease (GvHD) can be abrogated in mice 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; and, the mechanism by which an immature myeloid cell becomes a functional MDSC remains unknown. We have observed an increase (up to 8 fold) in a population of cells phenotypically resembling monoMDSCs (CD11b+/Ly6C+/Ly6G-) in the spleens and blood of mice mobilized with pegylated-murine-GM-CSF (peg-mGM-CSF). We hypothesized that this population of cells would have suppressive function similar to MDSCs in vitro and in vivo, and may have the potential to abrogate graft-versus-host disease (GvHD). To investigate the function of MDSCs found in spleens of C57/Bl6 (B6) mice treated with peg-mGM-CSF we performed CFSE based anti-CD3/CD28 antibody stimulated T-cell proliferation assays, mixed leukocyte reactions and transwell assays. We observed that CD11b+Ly6C+Ly6G- cells isolated from spleens of mice treated with peg-mGM-CSF have potent suppressive function in vitro that is contact dependent and abrogated by blocking ARG1 or iNOS. This suppressive effect was lost in APC stimulated MLRs using B6 T-cells and Balb/C stimulators (confirmed in two separate experiments). Furthermore, the in vivo potential of these putative MDSCs to abrogate murine GvHD was investigated using a B6 to Balb/C donor leukocyte infusion GvHD model. Adoptive transfer of purified splenic CD11b+Ly6C+Ly6G- cells from peg-mGM-CSF mobilized B6 donors along with an equivalent number of congenic T-cells failed to abrogate GvHD. We investigated timing of MDSC infusion in the B6 to Balb/C GvHD model and found no improvement in weight loss, GvHD score or survival in mice receiving 5×105 monoMDSCs IV on day 1, 6 or 10 after transplant compared to T-cells alone control (n = 5 – 10/group, Log rank, p= NS). To address in vivo function further in a bioluminescent imaging (BLI) tumor model. Balb/C recipients were injected SC with A20 cells mixed +/− monoMDSCs at a 1:10 ratio after lethal irradiation and T-cell deplete bone marrow on day 0. Donor T-cells were infused at day +11. The rate of tumor growth measured by photon flux was the same between subcutaneous tumors either with or without monoMDSCs. (two separate experiments, 5 mice/group). This in vivo data suggested that a critical factor present in vitro might be lacking or insufficient in vivo. To investigate the critical factor(s) present in vitro we performed T-cell proliferation assays in the presence of blocking antibodies against IFNy, TNFalpha, IL-10, GM-CSF and CD154. Only neutralization of IFNy resulted in negation of the suppressive effects of these cells. To investigate the source of IFNy production we used transgenic IFNy knockout mice as T-cell and MDSC donors. Proliferation of IFNy deficient T-cells was suppressed efficiently by wild-type (WT) MDSCs, and, neutralizing IFNy using a blocking antibody negated suppression. This suggested IFNy production by a cell within the putative MDSC sorted population might be critical for MDSC function. IFNy deficient peg-mGM-CSF mobilized CD11b+Ly6C+Ly6G- spleen cells failed to suppress WT or IFNy deficient T-cell proliferation. These results suggest a critical role for IFNy production by CD11b+Ly6C+Ly6G- myeloid cells in maintaining their suppressive phenotype in vitro and perhaps in vivo. Disclosures: No relevant conflicts of interest to declare.

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Pak2 Regulates MDSC Development and Function

Blood ◽

10.1182/blood.v128.22.705.705 ◽

2016 ◽

Vol 128 (22) ◽

pp. 705-705

Author(s):

Yi Zeng ◽

Seongmin Hahn ◽

Jessica Stokes ◽

Emely Hoffman ◽

Jonathan Chernoff ◽

...

Keyword(s):

Cell Proliferation ◽

T Cell ◽

Progenitor Cells ◽

Lineage Commitment ◽

T Cell Proliferation ◽

Myeloid Lineage ◽

Suppressive Function ◽

Gm Csf ◽

Group I

Abstract Myeloid derived suppressor cells (MDSCs) are a heterogeneous cell population at various stages of differentiation that can increase under various pathologic conditions such as cancer, infection or inflammation, displaying suppressive function. It is well recognized that MDSCs contribute to tumor evasion by suppressing cell-mediated immunity. Based on the differential expression of Ly6C and/or Ly6G in mice, MDSCs are characterized as granulocytic (CD11b+Ly6G+Ly6Clow) or monocytic MDSCs (CD11b+Ly6Glow/−Ly6Chi). These subsets induce T-cell hyporesponsiveness and can have various functions and distribution depending on their environment. Although much research has focused on the tumorigenic effects of MDSCs, studies on the regulation of their development during hematopoiesis remain limited. p21-activated kinases (Paks) are serine/threonine kinases that regulate diverse cellular activities including cytoskeletal remodeling, cell motility, proliferation, apoptosis and mitosis. Despite active research on pharmacological inhibition of group I Paks in treating solid tumors, few studies have examined the role of Paks in modulating normal hematopoiesis. Knowledge of the role of Pak2 in regulating long-term hematopoiesis and lineage commitment remains limited. Utilizing a conditional Pak2-KO murine model, we have previously demonstrated that Pak2 disruption in hematopoietic stem/progenitor cells (HSPCs) induces myeloid lineage skewing and CD11b+Gr1+ cell expansion in mice. Compared to mice reconstituted with wild type (WT) bone marrow (BM), mice transplanted with Pak2-KO BM displayed a significantly higher percentage of granulocyte-monocyte progenitors (GMPs) in the BM and higher numbers of CD11b+Gr1+ cells in the spleen. In this study, we demonstrated that CD11b+Gr1high cells isolated from the spleens of mice with Pak2-KO BM displayed significantly greater suppressive function on T cell proliferation in vitro, consistent with MDSC phenotype. There was a near 2-fold increase in the numbers of both granulocytic and monocytic splenic MDSCs in mice reconstituted with Pak2-KO BM. At HSPC level, Pak2-KO BM yielded greater than 3-fold more colonies in response to GM-CSF but not G-CSF or M-CSF when compared to WT cells, indicating selective hypersensitivity to GM-CSF. In parallel experiments, Pak2-KO and WT BM C-kit+ cells that were enriched for hematopoietic progenitor cells (HPCs) were cultured in liquid culture in the presence of GM-CSF. Pak2-KO BM C-kit+ cells yielded greater than 2-fold higher numbers of CD11b+Gr1+ MDSCs that displayed potent suppression on CD8+ T cell proliferation. These data demonstrate that Pak2 disruption increases HPC sensitivity to GM-CSF signaling and drives lineage commitment toward granulocyte-monocyte lineage thus promoting MDSC development. In addition, we have also found that Pak2 deficient MDSCs are more proliferative and more resistant to apoptosis when compared to WT CD11b+Gr1+cells, thus contributing to expansion of this population in vivo. Loss of Pak2 decreases MDSC sensitivity to apoptosis through differential regulation of multiple pro- and anti-apoptotic gene expression. Furthermore, Pak2 disruption down regulates the expression of IRF8, a well-described myeloid transcription factor. Together, our data indicate that loss of Pak2 promotes HPC myeloid lineage commitment and CD11b+Gr1+ MDSC proliferation while suppressing apoptotic cell death in these cells. Further studies are ongoing to determine the interaction between Pak2 and IRF8. Disclosures No relevant conflicts of interest to declare.

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LPSlow-Macrophages Alleviate the Outcome of Graft-Versus-Host Disease Without Aggravating Lymphoma Growth in Mice

Frontiers in Immunology ◽

10.3389/fimmu.2021.670776 ◽

2021 ◽

Vol 12 ◽

Author(s):

Mohamed Jeljeli ◽

Charlotte Chêne ◽

Sandrine Chouzenoux ◽

Marine Thomas ◽

Benjamin Segain ◽

...

Keyword(s):

Immune Response ◽

Cell Proliferation ◽

T Cell ◽

Myeloid Cells ◽

T Cell Proliferation ◽

Cell Phenotype ◽

Dependent Manner ◽

Host Disease ◽

And Function

Despite significant therapeutic advances, graft-versus-host disease (GvHD) remains the main life-threatening complication following allogeneic hematopoietic stem cell transplantation. The pathogenesis of GvHD is dominated by a dysregulated allogeneic immune response that drives fibrosis and autoimmunity in chronic forms. A multitude of cell therapy approaches, including infusion of myeloid cells, has been proposed to prevent GvHD through tolerance induction but yielded variable results. Myeloid cells like macrophages can be reprogrammed to develop adaptive-like features following antigenic challenge to reinforce or inhibit a subsequent immune response; a phenomenon termed ‘trained immunity’. Here we report that, whereas LPSlow-trained macrophages elicit a suppressor effect on allogeneic T cell proliferation and function in vitro in an IL-10-dependent manner, Bacille Calmette et Guérin (BCG)-trained macrophages exert an opposite effect. In a murine model of sclerodermatous chronic GvHD, LPSlow-trained macrophages attenuate clinical signs of GvHD with significant effects on T cell phenotype and function, autoantibodies production, and tissue fibrosis. Furthermore, infusion of LPSlow-macrophages significantly improves survival in mice with acute GvHD. Importantly, we also provide evidence that LPSlow-macrophages do not accelerate A20-lymphoma tumor growth, which is significantly reduced upon transfer of BCG-macrophages. Collectively, these data indicate that macrophages can be trained to significantly inhibit in vitro and in vivo allo-reactive T cell proliferation without exhibiting pro-tumoral effect, thereby opening the way to promising clinical applications.

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Comparison of Borrelia burgdorferi ultrasonicate and whole B. burgdorferi cells as a stimulus for T-Cell proliferation and GM-CSF secretion in vitro

Zentralblatt für Bakteriologie ◽

10.1016/s0934-8840(11)80374-9 ◽

1993 ◽

Vol 279 (3) ◽

pp. 417-425 ◽

Cited By ~ 6

Author(s):

Christoph Schempp ◽

Martin Owsianowsk ◽

Robert Lange ◽

Harald Gollnick

Keyword(s):

Cell Proliferation ◽

T Cell ◽

Borrelia Burgdorferi ◽

T Cell Proliferation ◽

Gm Csf

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

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0473 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A504-A504

Author(s):

Luis Carvajal ◽

Luciana Gneo ◽

Carmela De Santo ◽

Matt Perez ◽

Tracy Garron ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

T Cell ◽

Cancer Cell ◽

Suppressor Cells ◽

T Cell Proliferation ◽

Myeloid Derived Suppressor Cells ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony

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

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Keratinocytes Regulate the Threshold of Inflammation by Inhibiting T Cell Effector Functions

Cells ◽

10.3390/cells10071606 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1606

Author(s):

Peter Seiringer ◽

Stefanie Eyerich ◽

Kilian Eyerich ◽

Daniela Dittlein ◽

Anna Caroline Pilz ◽

...

Keyword(s):

Cell Proliferation ◽

T Cell ◽

Cytokine Production ◽

Nickel Sulfate ◽

Human Keratinocytes ◽

T Cell Proliferation ◽

Effector Functions ◽

The Impact ◽

Cell Effector

Whilst the importance of keratinocytes as a first-line defense has been widely investigated, little is known about their interactions with non-resident immune cells. In this study, the impact of human keratinocytes on T cell effector functions was analyzed in an antigen-specific in vitro model of allergic contact dermatitis (ACD) to nickel sulfate. Keratinocytes partially inhibited T cell proliferation and cytokine production. This effect was dependent on the keratinocyte/T cell ratio and was partially reversible by increasing the number of autologous dendritic cells. The inhibition of T cell proliferation by keratinocytes was independent of the T cell subtype and antigen presentation by different professional antigen-presenting cells. Autologous and heterologous keratinocytes showed comparable effects, while the fixation of keratinocytes with paraformaldehyde abrogated the immunosuppressive effect. The separation of keratinocytes and T cells by a transwell chamber, as well as a cell-free keratinocyte supernatant, inhibited T cell effector functions to the same amount as directly co-cultured keratinocytes, thus proving that soluble factor/s account for the observed suppressive effects. In conclusion, keratinocytes critically control the threshold of inflammatory processes in the skin by inhibiting T cell proliferation and cytokine production.

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Siplizumab, an Anti-CD2 Monoclonal Antibody, Induces a Unique Set of Immune Modulatory Effects Compared to Alemtuzumab and Rabbit Anti-Thymocyte Globulin In Vitro

Frontiers in Immunology ◽

10.3389/fimmu.2020.592553 ◽

2020 ◽

Vol 11 ◽

Author(s):

Christian Binder ◽

Felix Sellberg ◽

Filip Cvetkovski ◽

Erik Berglund ◽

David Berglund

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Mixed Lymphocyte Reaction ◽

T Cell Proliferation ◽

Allogeneic Mixed Lymphocyte Reaction ◽

Dependent Cell

Antibodies are commonly used in organ transplant induction therapy and to treat autoimmune disorders. The effects of some biologics on the human immune system remain incompletely characterized and a deeper understanding of their mechanisms of action may provide useful insights for their clinical application. The goal of this study was to contrast the mechanistic properties of siplizumab with Alemtuzumab and rabbit Anti-Thymocyte Globulin (rATG). Mechanistic assay systems investigating antibody-dependent cell-mediated cytotoxicity, antibody-dependent cell phagocytosis and complement-dependent cytotoxicity were used to characterize siplizumab. Further, functional effects of siplizumab, Alemtuzumab, and rATG were investigated in allogeneic mixed lymphocyte reaction. Changes in T cell activation, T cell proliferation and frequency of naïve T cells, memory T cells and regulatory T cells induced by siplizumab, Alemtuzumab and rATG in allogeneic mixed lymphocyte reaction were assessed via flow cytometry. Siplizumab depleted T cells, decreased T cell activation, inhibited T cell proliferation and enriched naïve and bona fide regulatory T cells. Neither Alemtuzumab nor rATG induced the same combination of functional effects. The results presented in this study should be used for further in vitro and in vivo investigations that guide the clinical use of immune modulatory biologics.

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IL-10 mRNA Engineered MSCs Demonstrate Enhanced Anti-Inflammation in an Acute GvHD Model

Cells ◽

10.3390/cells10113101 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3101

Author(s):

Cuiping Zhang ◽

Mina Delawary ◽

Peng Huang ◽

Jennifer A. Korchak ◽

Koji Suda ◽

...

Keyword(s):

Cell Proliferation ◽

T Cell ◽

Therapeutic Potential ◽

Immune Dysregulation ◽

T Cell Proliferation ◽

Immunomodulatory Effects ◽

Freezing And Thawing ◽

Mrna Transfection ◽

Clinical Conditions

Mesenchymal stem cells (MSCs) are used in various studies to induce immunomodulatory effects in clinical conditions associated with immune dysregulation such as graft versus host disease (GvHD). However, most of these clinical trials failed to go beyond early phase 2 studies because of limited efficacy. Various methods have been assessed to increase the potency of MSCs. IL-10 is an anti-inflammatory cytokine that is known to modulate immune responses in GvHD. In this study, we evaluated the feasibility of transfecting IL-10 mRNA to enhance MSC therapeutic potential. IL-10 mRNA engineered MSCs (eMSCs-IL10) maintained high levels of IL-10 expression even after freezing and thawing. IL-10 mRNA transfection did not appear to alter MSC intrinsic characteristics. eMSCs-IL10 significantly suppressed T cell proliferation relative to naïve MSCs in vitro. In a mouse model for GvHD, eMSCs-IL10 induced a decrease in plasma level of potent pro-inflammatory cytokines and inhibited CD4+ and CD8+ T cell proliferation in the spleen. In summary, our studies demonstrate the feasibility of potentiating MSCs to enhance their immunomodulatory effects by IL-10 mRNA transfection. The use of non-viral transfection may generate a safe and potent MSC product for treatment of clinical conditions associated with immune dysregulation such as GvHD.

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