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Open AccessArticle

Human Isogenic Cell Line Models for Neutrophils and Myeloid-Derived Suppressor Cells

by Yuting Zhang 1,2, Emily Wilt 2 and Xin Lu 1,2,3,*
1
Integrated Biomedical Sciences Graduate Program, University of Notre Dame, Notre Dame, IN 46556, USA
2
Department of Biological Sciences, Boler–Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA
3
Tumor Microenvironment and Metastasis Program, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN 46556, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(20), 7709; https://doi.org/10.3390/ijms21207709
Received: 20 September 2020 / Revised: 14 October 2020 / Accepted: 16 October 2020 / Published: 18 October 2020
(This article belongs to the Special Issue Current Trends of Neutrophil Biology 2.0)
Neutrophils with immunosuppressive activity are polymorphonuclear myeloid-derived suppressor cells (MDSCs) and may contribute to the resistance to cancer immunotherapy. A major gap for understanding and targeting these cells is the paucity of cell line models with cardinal features of human immunosuppressive neutrophils and their normal counterparts, especially in an isogenic manner. To address this issue, we employ the human promyelocytic cell line HL60 and use DMSO and cytokines (granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin 6 (IL6)) to induce the formation of either neutrophils or MDSCs. The induced MDSCs are CD11b+ CD33+ HLA-DR−/low and are heterogeneous for CD15 and CD14 expression. The induced MDSCs abrogate IL2 production and activation-induced cell death of the human T cell line Jurkat stimulated by CD3/CD28 antibodies, whereas the induced neutrophils enhance IL2 production from Jurkat cells. The induced MDSCs upregulate the expression of C/EBPβ, STAT3, VEGFR1, FATP2 and S100A8. Lastly, the immunosuppressive activity of the induced MDSCs is inhibited by all-trans retinoic acid and STAT3 inhibitor BP-1-102 through cellular differentiation and dedifferentiation mechanisms, respectively. Together, our study establishes a human isogenic cell line system for neutrophils and MDSCs and this system is expected to facilitate future studies on the biology and therapeutics of human immunosuppressive neutrophils. View Full-Text
Keywords: neutrophil; myeloid-derived suppressor cell; PMN-MDSC; HL60; Jurkat; GM-CSF; IL6; all-trans retinoic acid; STAT3 inhibitor neutrophil; myeloid-derived suppressor cell; PMN-MDSC; HL60; Jurkat; GM-CSF; IL6; all-trans retinoic acid; STAT3 inhibitor
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Zhang, Y.; Wilt, E.; Lu, X. Human Isogenic Cell Line Models for Neutrophils and Myeloid-Derived Suppressor Cells. Int. J. Mol. Sci. 2020, 21, 7709.

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