scholarly journals STAT3 regulates arginase-I in myeloid-derived suppressor cells from cancer patients

2013 ◽  
Vol 123 (4) ◽  
pp. 1580-1589 ◽  
Author(s):  
David Vasquez-Dunddel ◽  
Fan Pan ◽  
Qi Zeng ◽  
Mikhail Gorbounov ◽  
Emilia Albesiano ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Arginase I

scholarly journals Cisplatin inhibits frequency and suppressive activity of monocytic myeloid-derived suppressor cells in cancer patients

2021 ◽  
Vol 10 (1) ◽  
pp. 1935557
Author(s):  
Glenn F. Van Wigcheren ◽  
Nienke De Haas ◽  
Tom A. Mulder ◽  
Sophie K. Horrevorts ◽  
Martine Bloemendal ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Suppressive Activity

755 CXCR1 and CXCR2 chemokine receptor agonists produced by tumors induce neutrophil extracellular traps that interfere with immune cytotoxicity

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A803-A803 ◽  
Author(s):  
Alvaro Teijeira ◽  
Saray Garasa ◽  
Itziar Migueliz ◽  
Assunta Cirella ◽  
Ignacio Melero
Keyword(s):  
Cancer Patients ◽  
Tumor Cells ◽  
Mouse Models ◽  
Chemokine Receptor ◽  
Suppressor Cells ◽  
Neutrophil Extracellular Traps ◽  
Myeloid Derived Suppressor Cells ◽  
Extracellular Traps ◽  
Tumor Associated Neutrophils

BackgroundNeutrophils are expanded and abundant in an important fraction (up to 35% of patients) in cancer-bearing hosts. When neutrophils are expanded, they usually promote exert immunomodulatory functions promoting tumor progression and the generation of metastases. Neutrophils can undergo a specialized form of cell death called NETosis that is characterized by the extrusion of their DNA to contain infections. In cancer NETs have been described to promote metastases in mouse models. IL-8, a CXCR1/2 ligand clinically targeted by blocking antibodies, has been described to induce NETosis and is upregulated in many cancer patients. Our hypothesis is that chemokines secreted by cancer cells can mediate NETosis in tumor associated neutrophils and that NETs can be one of the immunomodulatory mechanisms provided by tumor associated neutrophils.MethodsNETosis induction of peripheral neutrophils and granulocytic myeloid derived suppressor cells by different chemotactic stimuli, tumor cell supernatants and cocultures upon CXCR1/2 blockade. NET immunodetection in mouse models and xenograft tumors upon CXCR1/2 blockade. In vitro tumor cytotoxicity assays in the presence/absence of NETs, and videomicroscopy studies in vitro and by intravital imaging to test NETs inhibition of immune cytotoxicity by immune-cell/target-cell inhibition. Tumor growth studies and metastases models in the presence of NETosis inhibitors and in combination with checkpoint blockade in mouse cancer models.ResultsUnder the influence of CXCR1 and CXCR2 chemokine receptor agonists and other chemotactic factors produced by tumors, neutrophils, and granulocytic myeloid-derived suppressor cells (MDSCs) from cancer patients extrude their neutrophil extracellular traps (NETs). In our hands, CXCR1 and CXCR2 agonists proved to be the major mediators of cancer-promoted NETosis. NETs wrap and coat tumor cells and shield them from cytotoxicity, as mediated by CD8+ T cells and natural killer (NK) cells, by obstructing contact between immune cells and the surrounding target cells. Tumor cells protected from cytotoxicity by NETs underlie successful cancer metastases in mice and the immunotherapeutic synergy of protein arginine deiminase 4 (PAD4) inhibitors, which curtail NETosis with immune checkpoint inhibitors. Intravital microscopy provides evidence of neutrophil NETs interfering cytolytic cytotoxic T lymphocytes (CTLs) and NK cell contacts with tumor cells.ConclusionsCXCR1 and 2 are the main receptors mediating NETosis of tumor associated neutrophils in our in-vitro and in vivo systems expressing high levels of CXCR1 and 2 ligands. NETs limit cancer cell cytotoxicity by impeding contacts with cancer cells.

scholarly journals Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients

2016 ◽  
Vol 1 (2) ◽  
pp. aaf8943-aaf8943 ◽  
Author(s):  
Thomas Condamine ◽  
George A. Dominguez ◽  
Je-In Youn ◽  
Andrew V. Kossenkov ◽  
Sridevi Mony ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Oxidized Ldl ◽  
Ldl Receptor ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells

scholarly journals Arginase I–Producing Myeloid-Derived Suppressor Cells in Renal Cell Carcinoma Are a Subpopulation of Activated Granulocytes

2009 ◽  
Vol 69 (4) ◽  
pp. 1553-1560 ◽  
Author(s):  
Paulo C. Rodriguez ◽  
Marc S. Ernstoff ◽  
Claudia Hernandez ◽  
Michael Atkins ◽  
Jovanny Zabaleta ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Arginase I

Significant Expansion of Myeloid Derived Suppressor Cells in Patients with High- Risk Breast Cancer Treated with Dose Dense Adjuvant Chemotherapy

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4653-4653
Author(s):  
James E Talmadge ◽  
Elizabeth Reed ◽  
Kenneth Cowan ◽  
Dmitry Gabrilovich ◽  
Phyllis Warkentin ◽  
...  
Keyword(s):  
T Cell ◽  
Cancer Patients ◽  
Mononuclear Cells ◽  
Flow Analysis ◽  
Suppressor Cells ◽  
Cell Number ◽  
Myeloid Derived Suppressor Cells ◽  
Breast Cancers ◽  
Dose Dense ◽  
And Function

Abstract Myeloid derived suppressor cells (MDSCs) have been reported to be expanded in cancer patients, following growth factor administration and after chemotherapy. These cells have been associated with a loss of T-cell number and function and provide one mechanism of immune evasion. We examined the effect of dose dense chemotherapy on immune phenotypes and function in patients with breast cancers 4 cms or larger and/or four or more involved nodes. The adjuvant therapy was dose-dense doxorubicin, cyclophosphamide (AC) followed by paclitaxel (P), then 33 doses of radiation (R). Blood samples were obtained and studied prior to therapy, 1 week post AC and 1, 15 and 21 weeks post P and then 3, 6 and 12 months later. Flow cytometric analyses of cellular phenotypes were done on these blood specimens and compared to the levels prior to therapeutic intervention and to normal age and sex matched donors. Twenty-three pts have been followed a median of 29 months (range 5.5–50.5 months) from study entry. Two patients relapsed 8 and 23 months after diagnosis. T-cell CD-4 numbers declined following AC from an average of 4.9±0.5 ×106/ml to 1.7±0.3×106/ml, but increased to an average of 2.7± 0.3 × 106/ml, 21 weeks after P or 12 weeks after R. In this study the MDSCs were defined as Lin- (CD3, CD19, CD14 and CD13), HLA-DR- and CD33+. The numbers of MDSCs, which in normal donors were 0.62±0.16×106/ml and in the cancer patients at diagnosis were 11.8±9.6×106/ml increased to 58.4±25.9×106/ml 15 weeks after R. They remained significantly elevated through one year after diagnosis when they were 27.3±12.3×106/ml. The majority of the MDSCs had a high side scatter and forward scatter by flow analysis suggesting a granulocytic commitment rather than a monocytic commitment. The increase in MDSC numbers was apparently associated with R as the numbers of MDSCs were not significantly increased by AC (15.7±13.5×106/ml) or P (10.9±6×106/ml) one week following completion of each cycle of dose dense therapy. In association with the increase in MDSCs there was a significant decrease in PHA proliferation by the peripherial blood mononuclear cells (MNCs) and suppressive activity by irradiated MNC for allergenic lymphocytes.

Targeting the glucose metabolism of monocytic myeloid-derived suppressor cells to stimulate cancer immunity.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 126-126
Author(s):  
Jaspreet Singh Grewal ◽  
Numan Al-Rayyan ◽  
Jamaal Ritchie ◽  
Paxton Schowe ◽  
Cam Falkner ◽  
...  
Keyword(s):  
T Cell ◽  
Cancer Patients ◽  
Transforming Growth Factor ◽  
Phase 1 ◽  
Suppressor Cells ◽  
Simultaneous Increase ◽  
Myeloid Derived Suppressor Cells ◽  
Suppressive Activity ◽  
Advanced Cancer Patients

126 Background: Myeloid derived suppressor cells (MDSCs) inhibit the expansion of tumor antigen-specific effector CD8+ T cells via different mechanisms including increased expression of arginase, transforming growth factor – β (TGF – β) and indoleamine 2,3-dioxygenase (IDO). Recently, MDSCs were found to over-express hypoxia inducible factor 1 alpha (HIF-1α) which is required for their differentiation. An essential transcriptional target of HIF-1α is 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) which synthesizes fructose 2,6-bisphosphate, an allosteric stimulator of glycolysis and of proliferation via stimulation of cyclin dependent kinase-1 (CDK1). We hypothesized that MDSCs might over-express PFKFB3 which in turn might be required for their function as T cell suppressors. Methods: We used monocytic MDSCs (M-MDSCs) induced by co-culture with A375 melanoma cells, M-MDSCs from metastatic melanoma patients, murine bone marrow MDSCs and splenic M-MDSCs from B16 F10 tumor bearing mice for our studies. T cell suppression assays were performed to analyze M-MDSC suppression and reversal following PFKFB3 blockade. Results: We found that M-MDSCs have increased PFKFB3 expression. We also found that PFK-158 administration in B16 (wild-type) melanoma-bearing mice results in a marked reduction in MDSCs and a simultaneous increase in CD8+ T cell infiltration in the tumors. We analyzed three advanced cancer patients for circulating MDSCs before and after PFK-158 administration as part of a multi-center phase 1 clinical trial. And, we found that the MDSCs were markedly reduced in each patient. In addition, we have generated data for MDSC suppressive activity following in vitro treatment with PFK-158 showing reversal of suppressive activity. Conclusions: Taken together, these data indicate that selective inhibition of PFKFB3 may be a novel approach to target MDSCs and combinations of PFKFB3 inhibitors with immunotherapies may be a rational strategy to promote durable immune-mediated remissions in cancer patients.

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