501 VISTA regulates the differentiation and suppressive function of myeloid-derived suppressor cells

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A536-A536
Author(s):  
Juan Dong ◽  
Cassandra Gilmore ◽  
Hieu Ta ◽  
Keman Zhang ◽  
Sarah Stone ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Signaling Pathways ◽  
Immune Checkpoint ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Myeloid Derived Suppressor Cells ◽  
Checkpoint Protein ◽  
Suppressive Function

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.

scholarly journals Pparα Ablation Suppresses T Cell Responses and Anti-Tumor Immunity By Compromising the Antigen-Presenting Properties of Tumor-Associated Macrophages

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 438-438
Author(s):  
Anthos Christofides ◽  
Carol Cao ◽  
Qi Wang ◽  
Natalia M Tijaro-Ovalle ◽  
Eirini Konstantinidou ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Suppressor Cells ◽  
T Cell Responses ◽  
Innate Immune ◽  
Myeloid Derived Suppressor Cells ◽  
Cell Responses

Abstract Peroxisome proliferator activated receptors (PPARs) are transcription factors that belong to nuclear hormone superfamily, with three distinct types identified: PPARapha (PPARα), PPARgamma (PPARγ), and PPARbeta/delta (PPARβ/δ). PPARs possess a critical role in the regulation of lipid metabolism, and thus play critical roles in the differentiation and fate of immune cells. PPARα is involved in lipid and carbohydrate metabolism and PPARα agonists, such as fibrates, have been used for the treatment of hypertriglyceridemia and cardiovascular diseases. PPARα has an anti-inflammatory role during infection, and similar to PPARγ, affects the polarization of macrophages. In acute myelogenous leukemia (AML), PPARα mutations correlate with chemoresistance, poor treatment outcomes and unfavorable prognosis. In experimental tumor models, it has been proposed that PPARα agonists might enhance anti-tumor T cell responses during PD-1 blocking immunotherapy. To dissect the mechanistic role of PPARα in tumor immunity, we used mice with global deletion of PPARα and examined tumor growth and profile of the immunological landscape, using various syngeneic tumor models. Significantly larger B16-F10 melanoma and MC-17 fibrosarcoma tumors were observed in PPARα KO mice compared with wild-type control, suggesting that PPARα deletion attenuated the immunological response against cancer. To dissect the role of PPARα in key populations of the innate and adaptive immune system involved in anti-tumor responses, we analyzed the immunological landscape of tumor, tumor draining lymph nodes (TDLN) and spleen, 14-16 days after tumor implantation. Assessment of CD4 + and CD8 + T cells, CD11b +F4/80 + tumor-associated macrophages (TAMs), CD11b +Ly6C hiLy6G - monocytic myeloid derived suppressor cells (M-MDSC), and CD11b +Ly6C loLy6G + polymorphonuclear myeloid derived suppressor cells (PMN-MDSC), by using flow cytometry, showed no quantitative differences between the two experimental groups. Functionally, MDSC from PPARα KO and WT mice showed comparable immunosuppressive properties as determined by suppression assay using splenocytes from OTI transgenic mice. However, PPARα KO TAMs demonstrated a less activated state, as determined by the lower expression levels of MHC-II that is critical for antigen presentation, and CD86 that is critical for T cell costimulation and prevention of T cell anergy and exhaustion. In agreement with these properties of TAMs, CD4 + T cells from TDLN of PPARα KO mice had diminished expression of activation markers, including PD-1, PD-L1 and ICOS, and numerically decreased central memory-like CD4 + T cells (T CM), compared to control tumor bearing mice. Furthermore, CD69, an emerging marker of T cell exhaustion, was significantly upregulated in CD4 + and CD8 + T cells from the TDLN of PPARα KO mice. To determine whether PPARα ablation altered the cell intrinsic properties of myeloid cells and/or T cells resulting in impaired anti-tumor function, we examined in vitro responses of isolated populations. In response to activation via TCR/CD3 and CD28, PPARα deficient T cells had no significant differences in expansion and cytokine production compared to control. In contrast, PPARα deficient Ly6C + monocytes isolated from the bone marrow displayed diminished responses to TLR-mediated signaling as determined by production of IL-6 and TNFα. Our in vitro and in vivo findings reveal a dominant role of PPARα in regulating the fate of innate immune cells thereby altering T cell responses and anti-tumor function. Our findings have implications for the development of new therapeutic approaches to enhance innate immune cell function for the improvement of cancer immunotherapy. Disclosures No relevant conflicts of interest to declare.

scholarly journals Expansion of Functional Myeloid-Derived Suppressor Cells in Controlled Human Malaria Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Carlos Lamsfus Calle ◽  
Rolf Fendel ◽  
Anurag Singh ◽  
Thomas L. Richie ◽  
Stephen L. Hoffman ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Malaria Infection ◽  
Malaria Vaccine ◽  
Suppressor Cells ◽  
T Cell Proliferation ◽  
Myeloid Derived Suppressor Cells ◽  
Controlled Human Malaria Infection

Malaria can cause life-threatening complications which are often associated with inflammatory reactions. More subtle, but also contributing to the burden of disease are chronic, often subclinical infections, which result in conditions like anemia and immunologic hyporesponsiveness. Although very frequent, such infections are difficult to study in endemic regions because of interaction with concurrent infections and immune responses. In particular, knowledge about mechanisms of malaria-induced immunosuppression is scarce. We measured circulating immune cells by cytometry in healthy, malaria-naïve, adult volunteers undergoing controlled human malaria infection (CHMI) with a focus on potentially immunosuppressive cells. Infectious Plasmodium falciparum (Pf) sporozoites (SPZ) (PfSPZ Challenge) were inoculated during two independent studies to assess malaria vaccine efficacy. Volunteers were followed daily until parasites were detected in the circulation by RT-qPCR. This allowed us to analyze immune responses during pre-patency and at very low parasite densities in malaria-naïve healthy adults. We observed a consistent increase in circulating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) in volunteers who developed P. falciparum blood stage parasitemia. The increase was independent of preceding vaccination with a pre-erythrocytic malaria vaccine. PMN-MDSC were functional, they suppressed CD4+ and CD8+ T cell proliferation as shown by ex-vivo co-cultivation with stimulated T cells. PMN-MDSC reduced T cell proliferation upon stimulation by about 50%. Interestingly, high circulating PMN-MDSC numbers were associated with lymphocytopenia. The number of circulating regulatory T cells (Treg) and monocytic MDSC (M-MDSC) showed no significant parasitemia-dependent variation. These results highlight PMN-MDSC in the peripheral circulation as an early indicator of infection during malaria. They suppress CD4+ and CD8+ T cell proliferation in vitro. Their contribution to immunosuppression in vivo in subclinical and uncomplicated malaria will be the subject of further research. Pre-emptive antimalarial pre-treatment of vaccinees to reverse malaria-associated PMN-MDSC immunosuppression could improve vaccine response in exposed individuals.

scholarly journals Granulocytic Myeloid-Derived Suppressor Cells Aggravate Tuberculosis Caused by Hypervirulent Mycobacteria

2020 ◽  
Author(s):  
Caio César Barbosa Bomfim ◽  
Eduardo Pinheiro Amaral ◽  
Igor Santiago-Carvalho ◽  
Gislane Almeida Santos ◽  
Érika Machado Salles ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Cell Function ◽  
Pulmonary Inflammation ◽  
Bacterial Load ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Partial Recovery ◽  
Myeloid Derived Suppressor Cells

Abstract Background The role of myeloid-derived suppressor cells (MDSCs) in severe tuberculosis patients who suffer from uncontrolled pulmonary inflammation caused by hypervirulent mycobacterial infection remains unclear. Methods This issue was addressed using C57BL/6 mice infected with highly virulent Mycobacterium bovis strain MP287/03. Results CD11b +GR1 int population increased in the bone marrow, blood and lungs during advanced disease. Pulmonary CD11b +GR1 int (Ly6G intLy6C int) cells showed granularity similar to neutrophils and expressed immature myeloid cell markers. These immature neutrophils harbored intracellular bacilli and were preferentially located in the alveoli. T cell suppression occurred concomitantly with CD11b +GR1 int cell accumulation in the lungs. Furthermore, lung and bone-marrow GR1 + cells suppressed both T cell proliferation and IFN-γ production in vitro. Anti-GR1 therapy given when MDSCs infiltrated the lungs prevented expansion and fusion of primary pulmonary lesions and the development of intragranulomatous caseous necrosis, along with increased mouse survival and partial recovery of T cell function. Lung bacterial load was reduced by anti-GR1 treatment, but mycobacteria released from the depleted cells proliferated extracellularly in the alveoli, forming cords and clumps. Conclusions Granulocytic MDSCs massively infiltrate the lungs during infection with hypervirulent mycobacteria, promoting bacterial growth and the development of inflammatory and necrotic lesions, and are promising targets for host-directed therapies.

Immature myeloid Gr-1+ CD11b+ cells from lipopolysaccharide-immunosuppressed mice acquire inhibitory activity in the bone marrow and migrate to lymph nodes to exert their suppressive function

2016 ◽  
Vol 130 (4) ◽  
pp. 259-271 ◽  
Author(s):  
Veronica I. Landoni ◽  
Daiana Martire-Greco ◽  
Nahuel Rodriguez-Rodrigues ◽  
Paula Chiarella ◽  
Pablo Schierloh ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Lymph Nodes ◽  
Inhibitory Activity ◽  
Suppressor Cells ◽  
T Cell Responses ◽  
Myeloid Derived Suppressor Cells ◽  
Suppressive Function ◽  
Cell Responses ◽  
Immunosuppressed Mice

LPS-induced immunosuppression, mimicking the state observed in patients with late sepsis, induced in bone marrow a population of myeloid-derived suppressor cells (Gr-1+ CD11b+) with the ability to inhibit T-cell responses and migrate to lymph nodes to exert their suppressive function.

A killer sidekick for antitumor T cells

2019 ◽  
Vol 11 (479) ◽  
pp. eaaw5325
Author(s):  
Christian S. Hinrichs
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Car T Cell ◽  
Car T

Engineered NK cells kill myeloid-derived suppressor cells to aid CAR-T cell antitumor responses.

scholarly journals Expansion of myeloid-derived suppressor cells in patients with severe coronavirus disease (COVID-19)

2020 ◽  
Vol 27 (11) ◽  
pp. 3196-3207 ◽  
Author(s):  
Chiara Agrati ◽  
Alessandra Sacchi ◽  
Veronica Bordoni ◽  
Eleonora Cimini ◽  
Stefania Notari ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Mononuclear Cells ◽  
Severe Disease ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Cell Functions ◽  
Convalescent Phase

Abstract SARS-CoV-2 is associated with a 3.4% mortality rate in patients with severe disease. The pathogenesis of severe cases remains unknown. We performed an in-depth prospective analysis of immune and inflammation markers in two patients with severe COVID-19 disease from presentation to convalescence. Peripheral blood from 18 SARS-CoV-2-infected patients, 9 with severe and 9 with mild COVID-19 disease, was obtained at admission and analyzed for T-cell activation profile, myeloid-derived suppressor cells (MDSCs) and cytokine profiles. MDSC functionality was tested in vitro. In four severe and in four mild patients, a longitudinal analysis was performed daily from the day of admission to the early convalescent phase. Early after admission severe patients showed neutrophilia, lymphopenia, increase in effector T cells, a persisting higher expression of CD95 on T cells, higher serum concentration of IL-6 and TGF-β, and a cytotoxic profile of NK and T cells compared with mild patients, suggesting a highly engaged immune response. Massive expansion of MDSCs was observed, up to 90% of total circulating mononuclear cells in patients with severe disease, and up to 25% in the patients with mild disease; the frequency decreasing with recovery. MDSCs suppressed T-cell functions, dampening excessive immune response. MDSCs decline at convalescent phase was associated to a reduction in TGF-β and to an increase of inflammatory cytokines in plasma samples. Substantial expansion of suppressor cells is seen in patients with severe COVID-19. Further studies are required to define their roles in reducing the excessive activation/inflammation, protection, influencing disease progression, potential to serve as biomarkers of disease severity, and new targets for immune and host-directed therapeutic approaches.

Increased Population Of Myeloid-Derived Suppressor Cells In Patients With Myelodysplastic Syndromes Overexpress ARG1 and Mediate CD8+ T Cell Inhibition

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5212-5212 ◽  
Author(s):  
Zonghong Shao ◽  
Huijuan Jiang ◽  
Rong Fu
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Myelodysplastic Syndromes ◽  
Suppressor Cells ◽  
Cd8 T Cell ◽  
Myeloid Derived Suppressor Cells ◽  
Normal Controls ◽  
Apoptosis Ratio

Abstract Objective To investigate the proportion and activation of myeloid- derived suppressor cells (MDSC) in bone marrow from patients with myelodysplastic syndromes (MDS). Methods The proportion of MDSC (Lin-HLA-DR-CD33+) in bone marrow of 30 MDS patients and 19 normal controls were measured by flow cytometry assay(FCM). MDSC and CD8+ T cell were isolated from bone marrow of 14 MDS patients and 14 normal controls among them by FCM and microbeads. The expressions of arginase 1(ARG1) and inducible nitric oxide synthase (iNOS) were analyzed by qPCR and western bolting. Co-cultures with CD8+ T cell were proved the MDSC-mediated inhibition of CD8+ T cell. Results MDS patient’s median MDSC were 7.29% which was higher than that of controls (2.91%). The expression of ARG1 and iNOS mRNA in MDSC of high-risk MDS patients was higher than that of low-risk MDS patients. But the protein of ARG1 was overexpressed rather than that of iNOS. After co-cultured, the apoptosis ratio of CD8+ T cells of MDS((64.17±4.86) %) was increased compared to pure CD8+ T cells ( (54.58±9.95)%). Further more, the production of IFN-γsecreted by CD8+ T cells co-cultured with MDSC ((551.94±47.39) pg/ml)was lower than that of pure CD8+ T cells ((586.04±46.65) pg/ml) There was no significant difference in level of TNF-βbetween co-cultured with MDSC and pure CD8+ cells. Conclusion The proportion of MDSC in bone marrow was increased significantly in MDS. MDSC overexpressed ARG1 in patients with MDS and correlated to the malignant degree of this disease. Further more, MDSC can increased the apoptosis ratio of CD8+ T cell, and inhibited the secretion of IFN-γ. These findings suggested MDSC mediated the response of immunosuppression in MDS. Disclosures: No relevant conflicts of interest to declare.

scholarly journals CLL-cells induce IDOhi CD14+HLA-DRlo myeloid-derived suppressor cells that inhibit T-cell responses and promote TRegs

Blood ◽  
2014 ◽  
Vol 124 (5) ◽  
pp. 750-760 ◽  
Author(s):  
Regina Jitschin ◽  
Martina Braun ◽  
Maike Büttner ◽  
Katja Dettmer-Wilde ◽  
Juliane Bricks ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Suppressor Cells ◽  
T Cell Responses ◽  
Myeloid Derived Suppressor Cells ◽  
Cell Responses ◽  
Key Points

Key Points Monocytic IDOhi MDSCs are increased in CLL patients, suppress T cells, and promote TReg induction. CLL cells induce conversion of monocytes into MDSCs suggesting bidirectional crosstalk between CLL cells, MDSCs, and TRegs.

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