scholarly journals Analysis of classical neutrophils and polymorphonuclear myeloid-derived suppressor cells in cancer patients and tumor-bearing mice

2021 ◽  
Vol 218 (4) ◽  
Author(s):  
Filippo Veglia ◽  
Ayumi Hashimoto ◽  
Harsh Dweep ◽  
Emilio Sanseviero ◽  
Alessandra De Leo ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Cell Mass ◽  
Suppressor Cells ◽  
Gene Signature ◽  
Polymorphonuclear Neutrophils ◽  
Myeloid Derived Suppressor Cells ◽  
Tumor Bearing ◽  
Selective Targeting ◽  
Negative Clinical Outcome ◽  
Cell Mass Spectrometry

In this study, using single-cell RNA-seq, cell mass spectrometry, flow cytometry, and functional analysis, we characterized the heterogeneity of polymorphonuclear neutrophils (PMNs) in cancer. We describe three populations of PMNs in tumor-bearing mice: classical PMNs, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), and activated PMN-MDSCs with potent immune suppressive activity. In spleens of mice, PMN-MDSCs gradually replaced PMNs during tumor progression. Activated PMN-MDSCs were found only in tumors, where they were present at the very early stages of the disease. These populations of PMNs in mice could be separated based on the expression of CD14. In peripheral blood of cancer patients, we identified two distinct populations of PMNs with characteristics of classical PMNs and PMN-MDSCs. The gene signature of tumor PMN-MDSCs was similar to that in mouse activated PMN-MDSCs and was closely associated with negative clinical outcome in cancer patients. Thus, we provide evidence that PMN-MDSCs are a distinct population of PMNs with unique features and potential for selective targeting opportunities.

scholarly journals Selective Targeting of Myeloid-Derived Suppressor Cells in Cancer Patients Using DS-8273a, an Agonistic TRAIL-R2 Antibody

2016 ◽  
Vol 23 (12) ◽  
pp. 2942-2950 ◽  
Author(s):  
George A. Dominguez ◽  
Thomas Condamine ◽  
Sridevi Mony ◽  
Ayumi Hashimoto ◽  
Fang Wang ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Selective Targeting

scholarly journals Identification of monocyte-like precursors of granulocytes in cancer as a mechanism for accumulation of PMN-MDSCs

2019 ◽  
Vol 216 (9) ◽  
pp. 2150-2169 ◽  
Author(s):  
Jérôme Mastio ◽  
Thomas Condamine ◽  
George Dominguez ◽  
Andrew V. Kossenkov ◽  
Laxminarasimha Donthireddy ◽  
...  
Keyword(s):  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Monocytic Cells ◽  
Tumor Bearing ◽  
Hla Dr ◽  
Selective Targeting ◽  
Selective Depletion ◽  
Monocytic Lineage

We have identified a precursor that differentiates into granulocytes in vitro and in vivo yet belongs to the monocytic lineage. We have termed these cells monocyte-like precursors of granulocytes (MLPGs). Under steady state conditions, MLPGs were absent in the spleen and barely detectable in the bone marrow (BM). In contrast, these cells significantly expanded in tumor-bearing mice and differentiated to polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Selective depletion of monocytic cells had no effect on the number of granulocytes in naive mice but decreased the population of PMN-MDSCs in tumor-bearing mice by 50%. The expansion of MLPGs was found to be controlled by the down-regulation of Rb1, but not IRF8, which is known to regulate the expansion of PMN-MDSCs from classic granulocyte precursors. In cancer patients, putative MLPGs were found within the population of CXCR1+CD15−CD14+HLA-DR−/lo monocytic cells. These findings describe a mechanism of abnormal myelopoiesis in cancer and suggest potential new approaches for selective targeting of MDSCs.

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 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
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