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      Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity

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          Abstract

          Myeloid-derived suppressor cells (MDSCs) are pathologically activated neutrophils and monocytes with potent immunosuppressive activity. They are implicated in the regulation of immune responses in many pathological conditions and are closely associated with poor clinical outcomes in cancer. Recent studies have indicated key distinctions between MDSCs and classical neutrophils and monocytes, and, in this Review, we discuss new data on the major genomic and metabolic characteristics of MDSCs. We explain how these characteristics shape MDSC function and could facilitate therapeutic targeting of these cells, particularly in cancer and in autoimmune diseases. Additionally, we briefly discuss emerging data on MDSC involvement in pregnancy, neonatal biology and COVID-19.

          Abstract

          This Review from Gabrilovich and colleagues discusses our current understanding of the development and functions of myeloid-derived suppressor cells (MDSCs). Recent work has identified unique metabolic properties and gene expression patterns in MDSCs that could help in the development of new therapies for cancer and autoimmunity.

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          Most cited references142

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          Succinate is an inflammatory signal that induces IL-1β through HIF-1α.

          Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis. Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1β but not tumour-necrosis factor-α in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the 'GABA (γ-aminobutyric acid) shunt' pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1α, an effect that is inhibited by 2-deoxyglucose, with interleukin-1β as an important target. Lipopolysaccharide also increases succinylation of several proteins. We therefore identify succinate as a metabolite in innate immune signalling, which enhances interleukin-1β production during inflammation.
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            Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards

            Myeloid-derived suppressor cells (MDSC) are a heterogeneous population expanded in cancer and other chronic inflammatory conditions. Here the authors identify the challenges and propose a set of minimal reporting guidelines for mouse and human MDSC.
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              Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN.

              TGF-beta blockade significantly slows tumor growth through many mechanisms, including activation of CD8(+) T cells and macrophages. Here, we show that TGF-beta blockade also increases neutrophil-attracting chemokines, resulting in an influx of CD11b(+)/Ly6G(+) tumor-associated neutrophils (TANs) that are hypersegmented, more cytotoxic to tumor cells, and express higher levels of proinflammatory cytokines. Accordingly, following TGF-beta blockade, depletion of these neutrophils significantly blunts antitumor effects of treatment and reduces CD8(+) T cell activation. In contrast, in control tumors, neutrophil depletion decreases tumor growth and results in more activated CD8(+) T cells intratumorally. Together, these data suggest that TGF-beta within the tumor microenvironment induces a population of TAN with a protumor phenotype. TGF-beta blockade results in the recruitment and activation of TANs with an antitumor phenotype.
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                Author and article information

                Contributors
                dmitry.gabrilovich@astrazeneca.com
                Journal
                Nat Rev Immunol
                Nat Rev Immunol
                Nature Reviews. Immunology
                Nature Publishing Group UK (London )
                1474-1733
                1474-1741
                1 February 2021
                : 1-14
                Affiliations
                [1 ]GRID grid.468198.a, ISNI 0000 0000 9891 5233, H. Lee Moffitt Cancer Center and Research Institute, ; Tampa, FL USA
                [2 ]GRID grid.251075.4, ISNI 0000 0001 1956 6678, Wistar Institute, ; Philadelphia, PA USA
                [3 ]GRID grid.418152.b, AstraZeneca, ; Gaithersburg, MD USA
                Author information
                http://orcid.org/0000-0001-9913-6407
                Article
                490
                10.1038/s41577-020-00490-y
                7849958
                33526920
                d1c3cbcd-f24e-44c2-8f08-0c06606084d6
                © Springer Nature Limited 2021

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 14 December 2020
                Categories
                Review Article

                tumour immunology,innate immune cells
                tumour immunology, innate immune cells

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