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Precision Medicine
Flow Cytometric Assays

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Myeloid-Derived Suppressor Cell Immunophenotyping Assays

Myeloid-derived suppressor cells (MDSCs) are recently discovered immunosuppressive neutrophils and monocytes activated by pathological conditions [1]. In classical myeloid cell activation, activation is robust, short-lived, and driven primarily by danger-associated molecular pattern (DAMPs), pathogen-associated molecular patterns (PAMPs) and TLRs [1,2]. In contrast, pathological activation is modest in strength and occurs as a result of persistent stimulation of myeloid cells through repeated exposure to inflammatory cytokines and growth factors such as GM-CSF and IL6 [1,2]. MDSCs are active in inflammation, infection, cancer, pregnancy, obesity, and autoimmune disease, and as such are gaining attention in clinical studies [1,3].

MDSCs are characterized by their potent ability to suppress the activation and function of other immune cells, such as T-cells and natural killer (NK) cells. They achieve this through a number of mechanisms, including the production of immunosuppressive molecules and the depletion of essential nutrients required for the proper functioning of immune cells. Unfortunately, their impressive immunosuppressive ability to help maintain immune homeostasis have also been reported correlate significantly with poor overall and progression free survival in various solid tumours [2]. The two classes of MDSCs have been named after their cell of origin due to their morphological and phenotypical resemblances: PMN-MDSCs (granulocytic/polymorphonuclear) and M-MDSCs (monocytic) [1-3].  

Polymorphonuclear Myeloid-Derived Suppressor Cells

Polymorphonuclear Myeloid-Derived Suppressor Cells (PMN-MDSCs) are morphologically similar to neutrophils and share some cell surface markers. However, they differ significantly in function: neutrophils function revolves around defence against pathogens, whereas PMN-MDSCs are primarily involved in immune regulation. PMN-MDSCs produce reactive oxygen species (ROS), arginase-1, and other immunosuppressive molecules to dampen T-cell activation and function [2]. PMN-MDSCs are mostly immature cells that exhibit plasticity, which means they can change their characteristics and function depending on the microenvironment [1]. Standard PMN-MDSC phenotypical markers in humans are CD11b+, CD14-, HLA-DRlo and CD15+/CD66b+[1, 3].

Monocytic Myeloid-Derived Suppressor Cells

Monocytic Myeloid-Derived Suppressor Cells (M-MDSCs) share morphological and phenotypical characteristics with monocytes [2]. M-MDSCs are involved in immune regulation and tolerance. Like PMN-MDSCs, M-MDSCs exert their immunosuppressive effects primarily through the production of immunosuppressive molecules, such as arginase, nitric oxide (NO), and reactive oxygen species (ROS) [2]. M-MDSCs are typically generated and expand in response to pro-inflammatory signals, such as cytokines like interleukin-6 (IL-6) and granulocyte-macrophage colony-stimulating factor (GM-CSF). M-MDSC phenotypical markers include CD11b+, CD14+, CD15-, CD33+ and HLA-DR lo/- [1, 3]. In tumour tissues, M-MDSC differentiate rapidly into TAM [2].

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References

[1] Kumar BV, Connors TJ, Farber DL. Human T cell development, localization, and function throughout life. Immunity. 2018 Feb 20;48(2):202-13.
[2] Caccamo N, Joosten SA, Ottenhoff TH, Dieli F. Atypical human effector/memory CD4+ T cells with a naive-like phenotype. Frontiers in immunology. 2018 Dec 3; 9:2832.
[3] Larbi A, Fulop T. From “truly naïve” to “exhausted senescent” T cells: when markers predict functionality. Cytometry Part A. 2014 Jan;85(1):25-35
[4] Van den Broek T, Borghans JA, Van Wijk F. The full spectrum of human naive T cells. Nature Reviews Immunology. 2018 Jun;18(6):363-73.
[5] Barry M, Bleackley RC. Cytotoxic T lymphocytes: all roads lead to death. Nature Reviews Immunology. 2002 Jun 1;2(6):401-9.
[6] Mousset CM, Hobo W, Woestenenk R, Preijers F, Dolstra H, van der Waart AB. Comprehensive phenotyping of T cells using flow cytometry. Cytometry Part A. 2019 Jun;95(6):647-54
[7] Schorer M, Kuchroo VK, Joller N. Role of co-stimulatory molecules in T helper cell differentiation. Co-signal Molecules in T Cell Activation: Immune Regulation in Health and Disease. 2019:153-77.
[8] Murphy K, Weaver C. (2017) Janeway's immunobiology (9th edition). New York and London: Garland Science.
[9] Wan YY, Flavell RA. How diverse—CD4 effector T cells and their functions. Journal of molecular cell biology. 2009 Oct 1;1(1):20-36.
[10] Végran F, Apetoh L, Ghiringhelli F. Th9 cells: a novel CD4 T-cell subset in the immune war against cancer. Cancer research. 2015 Feb 1;75(3):475-9.
[11] Laurent C, Fazilleau N, Brousset P. A novel subset of T-helper cells: follicular T-helper cells and their markers. Haematologica. 2010 Mar;95(3):356.
[12] Pepper M, Jenkins MK. Origins of CD4+ effector and central memory T cells. Nature immunology. 2011 Jun;12(6):467-71.
[13] Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T-cells and immune tolerance. cell. 2008 May 30;133(5):775-87.
[14] Santegoets SJ, Dijkgraaf EM, Battaglia A, Beckhove P, Britten CM, Gallimore A, Godkin A, Gouttefangeas C, de Gruijl TD, Koenen HJ, Scheffold A. Monitoring regulatory T-cells in clinical samples: consensus on an essential marker set and gating strategy for regulatory T cell analysis by flow cytometry. Cancer Immunology, Immunotherapy. 2015 Oct; 64:1271-86.
[15] Manuszak C, Brainard M, Thrash E, Hodi FS, Severgnini M. Standardized 11-color flow cytometry panel for the functional phenotyping of human T regulatory cells. Journal of Biological Methods. 2020;7(2).

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