Myeloid‐Derived Suppressor Cells

Abstract

Myeloid‐derived suppressor cells (MDSCs) are a heterogeneous population of myeloid progenitor cells and immature myeloid cells (IMCs) with a potent immunosuppressive activity against T‐cell responses. In health, IMCs differentiate into mature granulocytes, macrophages and dendritic cells, and these IMCs can be detected at low levels in circulation. However, different pathological conditions including cancer, infection, transplantation, autoimmune diseases and inflammation cause a disruption in the differentiation pathway of IMCs, leading to their accumulation. MDSCs exert their immunosuppressive function through the increased activity of immunosuppressive factors such as arginase‐1 and inducible nitric oxide synthase (iNOS), in addition to the increased production of nitric oxide (NO) and reactive oxygen/nitrogen species (ROS/RNS), and by modulating the production of various cytokines. The role of MDSCs in regulation of immune responses in both health and disease makes them an attractive therapeutic target in conquering various human diseases.

Key Concepts

  • MDSCs are a heterogeneous population of immature myeloid cells.
  • Much of our understanding of MDSCs came from cancer studies; however, recent work highlighted their significance in many other pathological conditions.
  • MDSCs are expanded in cancer and other pathological conditions owing to abnormal myelopoiesis.
  • Mice MDSCs are defined by the co‐expression of GR‐1 and CD11b.
  • Human MDSCs can be identified as CD11b+CD33+ HLA‐DR−/low, and further divided into granulocytic CD14 and monocytic CD14+ cells.
  • MDSCs exhibit a potent inhibitory effect on various T‐cell functions.
  • MDSCs exert their suppressive function through different mechanisms including expression of arginase 1 and inducible nitric oxide synthase and production of reactive oxygen species and nitric oxide.
  • Correlations between circulating/infiltrating MDSC levels and clinical parameters are contradictory owing to the heterogeneous nature of human MDSCs.
  • Some agents have been shown to reverse the immunosuppressive function or to directly target MDSCs for clinical benefits.

Keywords: MDSCs; phenotype; immunosuppression; cancer pathological conditions; therapeutics

Figure 1. Flow cytometric plots for characterisation of granulocytic and monocytic MDSCs. Peripheral blood sample from a healthy donor was stained with different mouse anti‐human antibodies against MDSC markers. These antibodies included Lin‐FITC, HLA‐DR‐PE, CD14‐PerCP‐Cy5.5, CD15‐APC, CD33‐PE‐Cy7 and CD11b‐APC eFluor 700 (all antibodies from eBioscience). After incubation, lysis buffer (BD FACS lysing solution) was added to lyse the red blood cells. Flow cytometric data were acquired on a FACSCanto II flow cytometers (BD Biosciences, USA), and data analysis was performed using BD FACSuite or FlowJo version X 10.0.7r2 software. The plots show G‐MDSCs, which are LinHLA‐DRCD11b+CD33+CD14CD15+, M‐MDSCs which are HLA‐DRCD33+CD11b+CD14+ and potential APCs which are HLA‐DR+CD33+CD11b+CD14+.
Figure 2. Mechanisms of MDSC suppression and enabling characteristics. ARG‐1 induces arginine deprivation and activity leads to CD3 down modulation and Treg expansion. iNOS induces nitric oxide production which leads to T‐cell apoptosis and inhibition of proliferation. MDSCs also compete with dendritic cells (DCs) for cysteine which is required by T cells for activation. Membrane‐bound TGF‐β leads to NK cell anergy.
Figure 3. Flow cytometric plots for characterisation of intracellular ARG‐1 release from different subsets. Peripheral blood sample from a healthy donor was stained with different mouse anti‐human antibodies against MDSC markers. These antibodies included HLA‐DR‐PE, CD14‐PerCP‐Cy5.5, CD15‐APC, CD33‐PE‐Cy7 and CD11b‐APC eFluor 700 (all antibodies from eBioscience). After incubation, lysis buffer (BD FACS lysing solution) was added to lyse the red blood cells. Following fixation and permeabilisation, intracellular staining against ARG‐1 was performed using sheep anti‐human/mouse arginase 1 fluorescein‐conjugated polyclonal antibody (R&D systems). Flow cytometric data were acquired on a FACSCanto II flow cytometers, and data analysis was performed using BD FACSuite or FlowJo version X 10.0.7r2 software. The plots show that ARG‐1 is made by HLA‐DRCD33+CD14CD15+CD11b+ MDSCs (population B), and not by HLA‐DR+CD33+CD14+CD15CD11b+ cells (population C) or HLA‐DRCD33CD14CD15CD11b cells (population A).
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Further Reading

Alizadeh D, Katsanis E and Larmonier N (2014) Chemotherapeutic targeting of myeloid‐derived suppressor cells. Oncoimmunology 3: e27359.

Dai J, El Gazzar M, Li GY, Moorman JP and Yao ZQ (2015) Myeloid‐derived suppressor cells: paradoxical roles in infection and immunity. Journal of Innate Immunity 7: 116–126.

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Pastula A and Marcinkiewicz J (2011) Myeloid‐derived suppressor cells: a double‐edged sword? International Journal of Experimental Pathology 92: 73–78.

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Toor, Salman M, and Elkord, Eyad(Oct 2015) Myeloid‐Derived Suppressor Cells. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024245]