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  • Review Article
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Myeloid-derived suppressor cells coming of age

Abstract

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells generated during a large array of pathologic conditions ranging from cancer to obesity. These cells represent a pathologic state of activation of monocytes and relatively immature neutrophils. MDSCs are characterized by a distinct set of genomic and biochemical features, and can, on the basis of recent findings, be distinguished by specific surface molecules. The salient feature of these cells is their ability to inhibit T cell function and thus contribute to the pathogenesis of various diseases. In this Review, we discuss the origin and nature of these cells; their distinctive features; and their biological roles in cancer, infectious diseases, autoimmunity, obesity and pregnancy.

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Fig. 1: Pathologic activation of neutrophils and monocytes.
Fig. 2: MDSC differentiation and accumulation.
Fig. 3: The role of MDSCs in obesity and pregnancy.

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References

  1. Gabrilovich, D. I. et al. The terminology issue for myeloid-derived suppressor cells. Cancer Res. 67, 425 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Gabrilovich, D. I., Ostrand-Rosenberg, S. & Bronte, V. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 12, 253–268 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Dumitru, C. A., Moses, K., Trellakis, S., Lang, S. & Brandau, S. Neutrophils and granulocytic myeloid-derived suppressor cells: immunophenotyping, cell biology and clinical relevance in human oncology. Cancer Immunol. Immunother. 61, 1155–1167 (2012).

    Article  CAS  PubMed  Google Scholar 

  4. Solito, S. et al. Myeloid-derived suppressor cell heterogeneity in human cancers. Ann. NY Acad. Sci. 1319, 47–65 (2014).

    Article  CAS  PubMed  Google Scholar 

  5. Bronte, V. et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat. Commun. 7, 12150 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Geissmann, F. et al. Development of monocytes, macrophages, and dendritic cells. Science 327, 656–661 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Veglia, F. & Gabrilovich, D. I. Dendritic cells in cancer: the role revisited. Curr. Opin. Immunol. 45, 43–51 (2017).

    Article  CAS  PubMed  Google Scholar 

  8. Barreda, D. R., Hanington, P. C. & Belosevic, M. Regulation of myeloid development and function by colony stimulating factors. Dev. Comp. Immunol. 28, 509–554 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Marvel, D. & Gabrilovich, D. I. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J. Clin. Invest. 125, 3356–3364 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Newton, K. & Dixit, V. M. Signaling in innate immunity and inflammation. Cold Spring Harb. Perspect. Biol. 4, a006049 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Kruger, P. et al. Neutrophils: between host defence, immune modulation, and tissue injury. PLoS Pathog. 11, e1004651 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Shi, C. & Pamer, E. G. Monocyte recruitment during infection and inflammation. Nat. Rev. Immunol. 11, 762–774 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Colotta, F., Allavena, P., Sica, A., Garlanda, C. & Mantovani, A. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 30, 1073–1081 (2009).

    Article  CAS  PubMed  Google Scholar 

  14. Landskron, G., de la Fuente, M., Thuwajit, P., Thuwajit, C. & Hermoso, M. A. Chronic inflammation and cytokines in the tumor microenvironment. J. Immunol. Res. 2014, 149185 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Umansky, V., Blattner, C., Gebhardt, C. & Utikal, J. The role of myeloid-derived suppressor cells (MDSC) in cancer progression. Vaccines (Basel) 4, E36 (2016).

    Article  Google Scholar 

  16. Youn, J. I., Collazo, M., Shalova, I. N., Biswas, S. K. & Gabrilovich, D. I. Characterization of the nature of granulocytic myeloid-derived suppressor cells in tumor-bearing mice. J. Leukoc. Biol. 91, 167–181 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Viale, A. et al. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 514, 628–632 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ortiz, M. L., Lu, L., Ramachandran, I. & Gabrilovich, D. I. Myeloid-derived suppressor cells in the development of lung cancer. Cancer Immunol. Res. 2, 50–58 (2014).

    Article  CAS  PubMed  Google Scholar 

  19. Netea, M. G. et al. Trained immunity: a program of innate immune memory in health and disease. Science 352, aaf1098 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Condamine, T. & Gabrilovich, D. I. Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol. 32, 19–25 (2011).

    Article  CAS  PubMed  Google Scholar 

  21. Bronte, V. et al. Unopposed production of granulocyte-macrophage colony-stimulating factor by tumors inhibits CD8+ T cell responses by dysregulating antigen-presenting cell maturation. J. Immunol. 162, 5728–5737 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Dolcetti, L. et al. Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF. Eur. J. Immunol. 40, 22–35 (2010).

    Article  CAS  PubMed  Google Scholar 

  23. Umansky, V. & Sevko, A. Tumor microenvironment and myeloid-derived suppressor cells. Cancer Microenviron. 6, 169–177 (2013).

    Article  CAS  PubMed  Google Scholar 

  24. Yan, D. et al. Polyunsaturated fatty acids promote the expansion of myeloid-derived suppressor cells by activating the JAK/STAT3 pathway. Eur. J. Immunol. 43, 2943–2955 (2013).

    Article  CAS  PubMed  Google Scholar 

  25. Condamine, T., Mastio, J. & Gabrilovich, D. I. Transcriptional regulation of myeloid-derived suppressor cells. J. Leukoc. Biol. 98, 913–922 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Haverkamp, J. M. et al. Myeloid-derived suppressor activity is mediated by monocytic lineages maintained by continuous inhibition of extrinsic and intrinsic death pathways. Immunity 41, 947–959 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ribechini, E. et al. Novel GM-CSF signals via IFN-γR/IRF-1 and AKT/mTOR license monocytes for suppressor function. Blood Advances 1, 947–960 (2017).This study demonstrates an actual example of the two-phase process in the generation of MDSCs.

    PubMed  PubMed Central  Google Scholar 

  28. Damuzzo, V. et al. Complexity and challenges in defining myeloid-derived suppressor cells. Cytometry B Clin. Cytom. 88, 77–91 (2015).This paper provides a detailed description of phenotypic characterization of MDSCs.

    Article  CAS  PubMed  Google Scholar 

  29. Fridlender, Z. G. et al. Polarization of tumor-associated neutrophil phenotype by TGF-β: “N1” versus “N2” TAN. Cancer Cell 16, 183–194 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cimen Bozkus, C., Elzey, B. D., Crist, S. A., Ellies, L. G. & Ratliff, T. L. Expression of cationic amino acid transporter 2 is required for myeloid-derived suppressor cell-mediated control of T cell immunity. J. Immunol. 195, 5237–5250 (2015).

    Article  CAS  PubMed  Google Scholar 

  31. Mairhofer, D. G. et al. Impaired gp100-Specific CD8+ T-cell responses in the presence of myeloid-derived suppressor cells in a spontaneous mouse melanoma model. J. Invest. Dermatol. 135, 2785–2793 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Raber, P. L. et al. Subpopulations of myeloid-derived suppressor cells impair T cell responses through independent nitric oxide-related pathways. Int. J. Cancer 134, 2853–2864 (2014).

    Article  CAS  PubMed  Google Scholar 

  33. Haile, L. A., Gamrekelashvili, J., Manns, M. P., Korangy, F. & Greten, T. F. CD49d is a new marker for distinct myeloid-derived suppressor cell subpopulations in mice. J. Immunol. 185, 203–210 (2010).

    Article  CAS  PubMed  Google Scholar 

  34. Movahedi, K. et al. Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood 111, 4233–4244 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9, 162–174 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Condamine, T. et al. Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients. Sci. Immunol. 1, aaf8943 (2016).This paper describes the identification of a specific marker of human PMN-MDSCs and the possibility of converting neutrophils to PMN-MDSCs by inducing ER stress.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Mandruzzato, S. et al. Toward harmonized phenotyping of human myeloid-derived suppressor cells by flow cytometry: results from an interim study. Cancer Immunol. Immunother. 65, 161–169 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Eruslanov, E. B., Singhal, S. & Albelda, S. M. Mouse versus human neutrophils in cancer: a major knowledge gap. Trends Cancer 3, 149–160 (2017).

    Article  PubMed  Google Scholar 

  39. Fridlender, Z. G. et al. Transcriptomic analysis comparing tumor-associated neutrophils with granulocytic myeloid-derived suppressor cells and normal neutrophils. PLoS One 7, e31524 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Gato, M. et al. Drafting the proteome landscape of myeloid-derived suppressor cells. Proteomics 16, 367–378 (2016).

    Article  CAS  PubMed  Google Scholar 

  41. Gato-Cañas, M. et al. A core of kinase-regulated interactomes defines the neoplastic MDSC lineage. Oncotarget 6, 27160–27175 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Nefedova, Y. et al. Hyperactivation of STAT3 is involved in abnormal differentiation of dendritic cells in cancer. J. Immunol. 172, 464–474 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Rébé, C., Végran, F., Berger, H. & Ghiringhelli, F. STAT3 activation: a key factor in tumor immunoescape. JAK-STAT 2, e23010 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Marigo, I. et al. Tumor-induced tolerance and immune suppression depend on the C/EBPβ transcription factor. Immunity 32, 790–802 (2010).

    Article  CAS  PubMed  Google Scholar 

  45. Kumar, V. et al. CD45 phosphatase inhibits STAT3 transcription factor activity in myeloid cells and promotes tumor-associated macrophage differentiation. Immunity 44, 303–315 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Netherby, C. S. et al. The granulocyte progenitor stage is a key target of IRF8-mediated regulation of myeloid-derived suppressor cell production. J. Immunol. 198, 4129–4139 (2017).

    Article  CAS  PubMed  Google Scholar 

  47. Ramji, D. P. & Foka, P. CCAAT/enhancer-binding proteins: structure, function and regulation. Biochem. J. 365, 561–575 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Abbasi, K. et al. Concomitant carotid endarterectomy and coronary artery bypass grafting versus staged carotid stenting followed by coronary artery bypass grafting. J. Cardiovasc. Surg. (Torino) 49, 285–288 (2008).

    CAS  Google Scholar 

  49. Youn, J. I. et al. Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer. Nat. Immunol. 14, 211–220 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Casbon, A. J. et al. Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils. Proc. Natl. Acad. Sci. USA 112, E566–E575 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Dufait, I. et al. Ex vivo generation of myeloid-derived suppressor cells that model the tumor immunosuppressive environment in colorectal cancer. Oncotarget 6, 12369–12382 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Casacuberta-Serra, S. et al. Myeloid-derived suppressor cells can be efficiently generated from human hematopoietic progenitors and peripheral blood monocytes. Immunol. Cell Biol. 95, 538–548 (2017).

    Article  CAS  PubMed  Google Scholar 

  53. Rodriguez, P. C. et al. Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma. J. Exp. Med. 202, 931–939 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Donkor, M. K. et al. Mammary tumor heterogeneity in the expansion of myeloid-derived suppressor cells. Int. Immunopharmacol. 9, 937–948 (2009).

    Article  CAS  PubMed  Google Scholar 

  55. Mao, Y. et al. Melanoma-educated CD14+ cells acquire a myeloid-derived suppressor cell phenotype through COX-2-dependent mechanisms. Cancer Res. 73, 3877–3887 (2013).

    Article  CAS  PubMed  Google Scholar 

  56. Hammami, I. et al. Immunosuppressive activity enhances central carbon metabolism and bioenergetics in myeloid-derived suppressor cells in vitro models. BMC Cell Biol. 13, 18 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hossain, F. et al. Inhibition of fatty acid oxidation modulates immunosuppressive functions of myeloid-derived suppressor cells and enhances cancer therapies. Cancer Immunol. Res. 3, 1236–1247 (2015).This paper shows the involvement of lipid metabolism in the functionality of MDSCs in cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Todd, D. J., Lee, A. H. & Glimcher, L. H. The endoplasmic reticulum stress response in immunity and autoimmunity. Nat. Rev. Immunol. 8, 663–674 (2008).

    Article  CAS  PubMed  Google Scholar 

  59. Grootjans, J., Kaser, A., Kaufman, R. J. & Blumberg, R. S. The unfolded protein response in immunity and inflammation. Nat. Rev. Immunol. 16, 469–484 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Cubillos-Ruiz, J. R. et al. ER stress sensor XBP1 controls anti-tumor immunity by disrupting dendritic cell homeostasis. Cell 161, 1527–1538 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Condamine, T. et al. ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis. J. Clin. Invest. 124, 2626–2639 (2014).Together with ref. 63, this study demonstrates the role of ER stress in MDSC function.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Lee, B. R. et al. Elevated endoplasmic reticulum stress reinforced immunosuppression in the tumor microenvironment via myeloid-derived suppressor cells. Oncotarget 5, 12331–12345 (2014).

    PubMed  PubMed Central  Google Scholar 

  63. Thevenot, P. T. et al. The stress-response sensor chop regulates the function and accumulation of myeloid-derived suppressor cells in tumors. Immunity 41, 389–401 (2014).Together with ref. 61, this study demonstrates the role of ER stress in MDSC function.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Dominguez, G. A. et al. Selective targeting of myeloid-derived suppressor cells in cancer patients using DS-8273a, an agonistic TRAIL-R2 antibody. Clin. Cancer Res. 23, 2942–2950 (2017).

    Article  CAS  PubMed  Google Scholar 

  65. Germano, G. et al. Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell 23, 249–262 (2013).

    Article  CAS  PubMed  Google Scholar 

  66. Marini, O. et al. Identification of granulocytic myeloid-derived suppressor cells (G-MDSCs) in the peripheral blood of Hodgkin and non-Hodgkin lymphoma patients. Oncotarget 7, 27676–27688 (2016).This paper reports that mature and activated neutrophils isolated from cancer patients have suppressive functions.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Marini, O. et al. Mature CD10+ and immature CD10 neutrophils present in G-CSF-treated donors display opposite effects on T cells. Blood 129, 1343–1356 (2017).

    Article  CAS  PubMed  Google Scholar 

  68. Noy, R. & Pollard, J. W. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41, 49–61 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Liu, Y. & Cao, X. The origin and function of tumor-associated macrophages. Cell. Mol. Immunol. 12, 1–4 (2015).

    Article  PubMed  CAS  Google Scholar 

  70. Ma, Y. et al. Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity 38, 729–741 (2013).

    Article  CAS  PubMed  Google Scholar 

  71. Marigo, I. et al. T cell cancer therapy requires CD40-CD40L activation of tumor necrosis factor and inducible nitric-oxide-synthase-producing dendritic cells. Cancer Cell 30, 651 (2016).

    Article  CAS  PubMed  Google Scholar 

  72. Tesone, A. J. et al. Satb1 overexpression drives tumor-promoting activities in cancer-associated dendritic cells. Cell Rep. 14, 1774–1786 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Sun, H. L. et al. Increased frequency and clinical significance of myeloid-derived suppressor cells in human colorectal carcinoma. World J. Gastroenterol. 18, 3303–3309 (2012).

    PubMed  PubMed Central  Google Scholar 

  74. Zhang, B. et al. Circulating and tumor-infiltrating myeloid-derived suppressor cells in patients with colorectal carcinoma. PLoS One 8, e57114 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Arihara, F. et al. Increase in CD14+HLA-DR–/low myeloid-derived suppressor cells in hepatocellular carcinoma patients and its impact on prognosis. Cancer Immunol. Immunother. 62, 1421–1430 (2013).

    Article  CAS  PubMed  Google Scholar 

  76. Diaz-Montero, C. M. et al. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol. Immunother. 58, 49–59 (2009).

    Article  CAS  PubMed  Google Scholar 

  77. Yang, G. et al. Accumulation of myeloid-derived suppressor cells (MDSCs) induced by low levels of IL-6 correlates with poor prognosis in bladder cancer. Oncotarget 8, 38378–38388 (2017).

    PubMed  PubMed Central  Google Scholar 

  78. Angell, T. E. et al. Circulating myeloid-derived suppressor cells predict differentiated thyroid cancer diagnosis and extent. Thyroid 26, 381–389 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Huang, A. et al. Increased CD14+HLA-DR–/low myeloid-derived suppressor cells correlate with extrathoracic metastasis and poor response to chemotherapy in non-small cell lung cancer patients. Cancer Immunol. Immunother. 62, 1439–1451 (2013).

    Article  CAS  PubMed  Google Scholar 

  80. Jordan, K. R. et al. Myeloid-derived suppressor cells are associated with disease progression and decreased overall survival in advanced-stage melanoma patients. Cancer Immunol. Immunother. 62, 1711–1722 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Zhang, S. et al. The role of myeloid-derived suppressor cells in patients with solid tumors: a meta-analysis. PLoS One 11, e0164514 (2016).A meta-analysis of the association between MDSC accumulation and clinical outcome in people with cancer.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Tada, K. et al. Pretreatment immune status correlates with progression-free survival in chemotherapy-treated metastatic colorectal cancer patients. Cancer Immunol. Res. 4, 592–599 (2016).

    Article  CAS  PubMed  Google Scholar 

  83. Zhang, H. et al. CXCL2/MIF-CXCR2 signaling promotes the recruitment of myeloid-derived suppressor cells and is correlated with prognosis in bladder cancer. Oncogene 36, 2095–2104 (2017).

    Article  CAS  PubMed  Google Scholar 

  84. Kawano, M. et al. The significance of G-CSF expression and myeloid-derived suppressor cells in the chemoresistance of uterine cervical cancer. Sci. Rep. 5, 18217 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Li, X. et al. Neutrophil count is associated with myeloid derived suppressor cell level and presents prognostic value of for hepatocellular carcinoma patients. Oncotarget 8, 24380–24388 (2017).

    PubMed  PubMed Central  Google Scholar 

  86. Wang, Z. et al. Tumor-induced CD14+HLA-DR–/low myeloid-derived suppressor cells correlate with tumor progression and outcome of therapy in multiple myeloma patients. Cancer Immunol. Immunother. 64, 389–399 (2015).

    Article  CAS  PubMed  Google Scholar 

  87. Wu, C. et al. Prognostic significance of peripheral monocytic myeloid-derived suppressor cells and monocytes in patients newly diagnosed with diffuse large B-cell lymphoma. Int. J. Clin. Exp. Med. 8, 15173–15181 (2015).

    PubMed  PubMed Central  Google Scholar 

  88. Galdiero, M. R. et al. Occurrence and significance of tumor-associated neutrophils in patients with colorectal cancer. Int. J. Cancer 139, 446–456 (2016).

    Article  CAS  PubMed  Google Scholar 

  89. Hurt, B., Schulick, R., Edil, B., El Kasmi, K. C. & Barnett, C. Jr. Cancer-promoting mechanisms of tumor-associated neutrophils. Am. J. Surg. 214, 938–944 (2017).

    Article  PubMed  Google Scholar 

  90. Wang, J. & Yang, J. Identification of CD4+CD25+CD127 regulatory T cells and CD14+HLA-DR–/low myeloid-derived suppressor cells and their roles in the prognosis of breast cancer. Biomed. Rep. 5, 208–212 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Chen, M. F. et al. IL-6-stimulated CD11b+CD14+HLA-DR myeloid-derived suppressor cells, are associated with progression and poor prognosis in squamous cell carcinoma of the esophagus. Oncotarget 5, 8716–8728 (2014).

    PubMed  PubMed Central  Google Scholar 

  92. Lee, S. E. et al. Circulating immune cell phenotype can predict the outcome of lenalidomide plus low-dose dexamethasone treatment in patients with refractory/relapsed multiple myeloma. Cancer Immunol. Immunother. 65, 983–994 (2016).

    Article  CAS  PubMed  Google Scholar 

  93. Romano, A. et al. Circulating myeloid-derived suppressor cells correlate with clinical outcome in Hodgkin lymphoma patients treated up-front with a risk-adapted strategy. Br. J. Haematol. 168, 689–700 (2015).

    Article  CAS  PubMed  Google Scholar 

  94. Wang, D., An, G., Xie, S., Yao, Y. & Feng, G. The clinical and prognostic significance of CD14+HLA-DR–/low myeloid-derived suppressor cells in hepatocellular carcinoma patients receiving radiotherapy. Tumour Biol. 37, 10427–10433 (2016).

    Article  CAS  PubMed  Google Scholar 

  95. Butterfield, L. H. et al. Immune correlates of GM-CSF and melanoma peptide vaccination in a randomized trial for the adjuvant therapy of resected high-risk melanoma (E4697). Clin. Cancer Res. 23, 5034–5043 (2017).

    Article  CAS  PubMed  Google Scholar 

  96. Kimura, T. et al. MUC1 vaccine for individuals with advanced adenoma of the colon: a cancer immunoprevention feasibility study. Cancer Prev. Res. (Phila.) 6, 18–26 (2013).

    Article  CAS  Google Scholar 

  97. de Coaña, Y. P. et al. Ipilimumab treatment decreases monocytic MDSCs and increases CD8 effector memory T cells in long-term survivors with advanced melanoma. Oncotarget 8, 21539–21553 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Sade-Feldman, M. et al. Clinical significance of circulating CD33+CD11b+HLA-DR myeloid cells in patients with stage IV melanoma treated with ipilimumab. Clin. Cancer Res. 22, 5661–5672 (2016).

    Article  CAS  PubMed  Google Scholar 

  99. Martens, A. et al. Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab. Clin. Cancer Res. 22, 2908–2918 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Weber, J. et al. Phase I/II study of metastatic melanoma patients treated with nivolumab who had progressed after ipilimumab. Cancer Immunol. Res. 4, 345–353 (2016).This paper describes the association of high numbers of MDSCs with response and survival after treatment with PD-1 antibody in patients in which disease had progressed with anti-CTLA4 therapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Iida, Y. et al. Contrasting effects of cyclophosphamide on anti-CTL-associated protein 4 blockade therapy in two mouse tumor models. Cancer Sci. 108, 1974–1984 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Highfill, S. L. et al. Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. Sci. Transl. Med. 6, 237ra67 (2014).A demonstration of the therapeutic effect of blocking MDSC trafficking.

    Article  PubMed  CAS  Google Scholar 

  103. Du Four, S. et al. Combined VEGFR and CTLA-4 blockade increases the antigen-presenting function of intratumoral DCs and reduces the suppressive capacity of intratumoral MDSCs. Am. J. Cancer Res. 6, 2514–2531 (2016).

    PubMed  PubMed Central  Google Scholar 

  104. Davis, R. J. et al. Anti-PD-L1 efficacy can be enhanced by inhibition of myeloid-derived suppressor cells with a selective inhibitor of PI3Kδ/γ. Cancer Res. 77, 2607–2619 (2017).This paper describes the therapeutic effect in mice after downregulation of MDSCs with PI3K inhibitor.

    Article  CAS  PubMed  Google Scholar 

  105. Lu, X. et al. Effective combinatorial immunotherapy for castration-resistant prostate cancer. Nature 543, 728–732 (2017).This study demonstrates the important role of MDSCs in a prostate cancer model, as well as the potential therapeutic benefit of targeting these cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Kamran, N. et al. Immunosuppressive myeloid cells’ blockade in the glioma microenvironment enhances the efficacy of immune-stimulatory gene therapy. Mol. Ther. 25, 232–248 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Ost, M. et al. Myeloid-derived suppressor cells in bacterial infections. Front. Cell. Infect. Microbiol. 6, 37 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Tebartz, C. et al. A major role for myeloid-derived suppressor cells and a minor role for regulatory T cells in immunosuppression during Staphylococcus aureus infection. J. Immunol. 194, 1100–1111 (2015).

    Article  CAS  PubMed  Google Scholar 

  109. Heim, C. E. et al. Myeloid-derived suppressor cells contribute to Staphylococcus aureus orthopedic biofilm infection. J. Immunol. 192, 3778–3792 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Dietlin, T. A. et al. Mycobacteria-induced Gr-1+ subsets from distinct myeloid lineages have opposite effects on T cell expansion. J. Leukoc. Biol. 81, 1205–1212 (2007).

    Article  CAS  PubMed  Google Scholar 

  111. Janols, H. et al. A high frequency of MDSCs in sepsis patients, with the granulocytic subtype dominating in Gram-positive cases. J. Leukoc. Biol. 96, 685–693 (2014).

    Article  PubMed  CAS  Google Scholar 

  112. Uhel, F. et al. Early expansion of circulating granulocytic myeloid-derived suppressor cells predicts development of nosocomial infections in patients with sepsis. Am. J. Respir. Crit. Care Med. 196, 315–327 (2017).

    Article  PubMed  Google Scholar 

  113. Poe, S. L. et al. STAT1-regulated lung MDSC-like cells produce IL-10 and efferocytose apoptotic neutrophils with relevance in resolution of bacterial pneumonia. Mucosal Immunol. 6, 189–199 (2013).

    Article  CAS  PubMed  Google Scholar 

  114. Rieber, N. et al. Pathogenic fungi regulate immunity by inducing neutrophilic myeloid-derived suppressor cells. Cell Host Microbe 17, 507–514 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Singh, A. et al. Differential regulation of myeloid-derived suppressor cells by Candida species. Front. Microbiol. 7, 1624 (2016).

    PubMed  PubMed Central  Google Scholar 

  116. Zhang, C. et al. Accumulation of myeloid-derived suppressor cells in the lungs during Pneumocystis pneumonia. Infect. Immun. 80, 3634–3641 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Cai, W. et al. Clinical significance and functional studies of myeloid-derived suppressor cells in chronic hepatitis C patients. J. Clin. Immunol. 33, 798–808 (2013).

    Article  CAS  PubMed  Google Scholar 

  118. Tacke, R. S. et al. Myeloid suppressor cells induced by hepatitis C virus suppress T-cell responses through the production of reactive oxygen species. Hepatology 55, 343–353 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Goh, C. C. et al. Hepatitis C virus-induced myeloid-derived suppressor cells suppress NK cell IFN-γ production by altering cellular metabolism via arginase-1. J. Immunol. 196, 2283–2292 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Goh, Y. S. et al. Bactericidal immunity to Salmonella in Africans and mechanisms causing its failure in HIV infection. PLoS Negl. Trop. Dis. 10, e0004604 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Zhai, N. et al. Hepatitis C virus induces MDSCs-like monocytes through TLR2/PI3K/AKT/STAT3 signaling. PLoS One 12, e0170516 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Qin, A. et al. Expansion of monocytic myeloid-derived suppressor cells dampens T cell function in HIV-1-seropositive individuals. J. Virol. 87, 1477–1490 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Tumino, N. et al. In HIV-positive patients, myeloid-derived suppressor cells induce T-cell anergy by suppressing CD3ζ expression through ELF-1 inhibition. AIDS 29, 2397–2407 (2015).

    Article  CAS  PubMed  Google Scholar 

  124. Garg, A. & Spector, S. A. HIV type 1 gp120-induced expansion of myeloid derived suppressor cells is dependent on interleukin 6 and suppresses immunity. J. Infect. Dis. 209, 441–451 (2014).

    Article  CAS  PubMed  Google Scholar 

  125. Wang, L. et al. Expansion of myeloid-derived suppressor cells promotes differentiation of regulatory T cells in HIV-1+ individuals. AIDS 30, 1521–1531 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Zhang, Z. N. et al. Myeloid-derived suppressor cells associated with disease progression in primary HIV infection: PD-L1 blockade attenuates inhibition. J. Acquir. Immune Defic. Syndr. 76, 200–208 (2017).

    Article  PubMed  Google Scholar 

  127. Tumino, N. et al. Granulocytic myeloid-derived suppressor cells increased in early phases of primary HIV infection depending on TRAIL plasma level. J. Acquir. Immune Defic. Syndr. 74, 575–582 (2017).

    Article  CAS  PubMed  Google Scholar 

  128. Nicholson, L. B., Raveney, B. J. & Munder, M. Monocyte dependent regulation of autoimmune inflammation. Curr. Mol. Med. 9, 23–29 (2009).

    Article  CAS  PubMed  Google Scholar 

  129. Iwata, Y. et al. Involvement of CD11b+ GR-1low cells in autoimmune disorder in MRL-Faslpr mouse. Clin. Exp. Nephrol. 14, 411–417 (2010).

    Article  PubMed  Google Scholar 

  130. Park, M. J. et al. Myeloid-derived suppressor cells induce the expansion of regulatory B cells and ameliorate autoimmunity in the sanroque mouse model of systemic lupus erythematosus. Arthritis Rheumatol. 68, 2717–2727 (2016).

    Article  CAS  PubMed  Google Scholar 

  131. Vlachou, K. et al. Elimination of granulocytic myeloid-derived suppressor cells in lupus-prone mice linked to reactive oxygen species-dependent extracellular trap formation. Arthritis Rheumatol. 68, 449–461 (2016).

    Article  CAS  PubMed  Google Scholar 

  132. Wu, H. et al. Arginase-1-dependent promotion of TH17 differentiation and disease progression by MDSCs in systemic lupus erythematosus. Sci. Transl. Med. 8, 331ra340 (2016).

    Google Scholar 

  133. Zhang, H. et al. Myeloid-derived suppressor cells are proinflammatory and regulate collagen-induced arthritis through manipulating Th17 cell differentiation. Clin. Immunol. 157, 175–186 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Guo, C. et al. Myeloid-derived suppressor cells have a proinflammatory role in the pathogenesis of autoimmune arthritis. Ann. Rheum. Dis. 75, 278–285 (2016).

    Article  CAS  PubMed  Google Scholar 

  135. Kurkó, J. et al. Identification of myeloid-derived suppressor cells in the synovial fluid of patients with rheumatoid arthritis: a pilot study. BMC Musculoskelet. Disord. 15, 281 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  136. Egelston, C. et al. Suppression of dendritic cell maturation and T cell proliferation by synovial fluid myeloid cells from mice with autoimmune arthritis. Arthritis Rheum. 64, 3179–3188 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Jiao, Z. et al. Increased circulating myeloid-derived suppressor cells correlated negatively with Th17 cells in patients with rheumatoid arthritis. Scand. J. Rheumatol. 42, 85–90 (2013).

    Article  CAS  PubMed  Google Scholar 

  138. Guan, Q. et al. The role and potential therapeutic application of myeloid-derived suppressor cells in TNBS-induced colitis. J. Leukoc. Biol. 94, 803–811 (2013).

    Article  CAS  PubMed  Google Scholar 

  139. Kontaki, E. et al. Aberrant function of myeloid-derived suppressor cells (MDSCs) in experimental colitis and in inflammatory bowel disease (IBD) immune responses. Autoimmunity 50, 170–181 (2017).

    Article  CAS  PubMed  Google Scholar 

  140. Rader, D. J. Effect of insulin resistance, dyslipidemia, and intra-abdominal adiposity on the development of cardiovascular disease and diabetes mellitus. Am. J. Med. 120, S12–S18 (2007).

    Article  CAS  PubMed  Google Scholar 

  141. Renehan, A. G., Roberts, D. L. & Dive, C. Obesity and cancer: pathophysiological and biological mechanisms. Arch. Physiol. Biochem. 114, 71–83 (2008).

    Article  CAS  PubMed  Google Scholar 

  142. Yin, B. et al. Myeloid-derived suppressor cells prevent type 1 diabetes in murine models. J. Immunol. 185, 5828–5834 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Xia, S. et al. Gr-1+ CD11b+ myeloid-derived suppressor cells suppress inflammation and promote insulin sensitivity in obesity. J. Biol. Chem. 286, 23591–23599 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Chen, S. et al. Diminished immune response to vaccinations in obesity: role of myeloid-derived suppressor and other myeloid cells. Obes. Res. Clin. Pract. 9, 35–44 (2015).

    Article  PubMed  Google Scholar 

  145. Bao, Y., Mo, J., Ruan, L. & Li, G. Increased monocytic CD14+HLADRlow/– myeloid-derived suppressor cells in obesity. Mol. Med. Rep. 11, 2322–2328 (2015).

    Article  CAS  PubMed  Google Scholar 

  146. Quail, D. F. et al. Obesity alters the lung myeloid cell landscape to enhance breast cancer metastasis through IL5 and GM-CSF. Nat. Cell Biol. 19, 974–987 (2017).

    Article  CAS  PubMed  Google Scholar 

  147. Okwan-Duodu, D., Umpierrez, G. E., Brawley, O. W. & Diaz, R. Obesity-driven inflammation and cancer risk: role of myeloid derived suppressor cells and alternately activated macrophages. Am. J. Cancer Res. 3, 21–33 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Thomas, D. & Apovian, C. Macrophage functions in lean and obese adipose tissue. Metabolism 72, 120–143 (2017).

    Article  CAS  PubMed  Google Scholar 

  149. Lu, H. et al. Macrophages recruited via CCR2 produce insulin-like growth factor-1 to repair acute skeletal muscle injury. FASEB J. 25, 358–369 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Satoh, T. et al. The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat. Immunol. 11, 936–944 (2010).

    Article  CAS  PubMed  Google Scholar 

  151. Boutens, L. & Stienstra, R. Adipose tissue macrophages: going off track during obesity. Diabetologia 59, 879–894 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Pirvulescu, M. M. et al. Subendothelial resistin enhances monocyte transmigration in a co-culture of human endothelial and smooth muscle cells by mechanisms involving fractalkine, MCP-1 and activation of TLR4 and Gi/o proteins signaling. Int. J. Biochem. Cell Biol. 50, 29–37 (2014).

    Article  CAS  PubMed  Google Scholar 

  153. Galván, G. C. et al. Effects of obesity on the regulation of macrophage population in the prostate tumor microenvironment. Nutr. Cancer 69, 996–1002 (2017).

    Article  PubMed  CAS  Google Scholar 

  154. Ghaebi, M. et al. Immune regulatory network in successful pregnancy and reproductive failures. Biomed. Pharmacother. 88, 61–73 (2017).

    Article  CAS  PubMed  Google Scholar 

  155. Fainaru, O., Hantisteanu, S. & Hallak, M. Immature myeloid cells accumulate in mouse placenta and promote angiogenesis. Am. J. Obstet. Gynecol. 204, 544.e518–544.e23 (2011).

    Article  CAS  Google Scholar 

  156. Pan, T. et al. Myeloid-derived suppressor cells are essential for maintaining feto-maternal immunotolerance via STAT3 signaling in mice. J. Leukoc. Biol. 100, 499–511 (2016).Together with ref. 160, this study demonstrates the role of MDSCs in the maintenance of feto-maternal tolerance.

    Article  CAS  PubMed  Google Scholar 

  157. Kang, X. et al. CXCR2-mediated granulocytic myeloid-derived suppressor cells’ functional characterization and their role in maternal fetal interface. DNA Cell Biol. 35, 358–365 (2016).

    Article  CAS  PubMed  Google Scholar 

  158. Pan, T. et al. 17β-Oestradiol enhances the expansion and activation of myeloid-derived suppressor cells via signal transducer and activator of transcription (STAT)-3 signalling in human pregnancy. Clin. Exp. Immunol. 185, 86–97 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Kang, X. et al. Granulocytic myeloid-derived suppressor cells maintain feto-maternal tolerance by inducing Foxp3 expression in CD4+CD25 T cells by activation of the TGF-β/β-catenin pathway. Mol. Hum. Reprod. 22, 499–511 (2016).

    Article  PubMed  Google Scholar 

  160. Ostrand-Rosenberg, S. et al. Frontline science: myeloid-derived suppressor cells (MDSCs) facilitate maternal-fetal tolerance in mice. J. Leukoc. Biol. 101, 1091–1101 (2017).Together with ref. 156, this study demonstrates the role of MDSCs in the maintenance of feto-maternal tolerance.

    Article  CAS  PubMed  Google Scholar 

  161. Gantt, S., Gervassi, A., Jaspan, H. & Horton, H. The role of myeloid-derived suppressor cells in immune ontogeny. Front. Immunol. 5, 387 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. Bartmann, C. et al. CD33+/HLA-DRneg and CD33+/HLA-DR+/– cells: rare populations in the human decidua with characteristics of MDSC. Am. J. Reprod. Immunol. 75, 539–556 (2016).

    Article  CAS  PubMed  Google Scholar 

  163. Köstlin, N. et al. Granulocytic myeloid derived suppressor cells expand in human pregnancy and modulate T-cell responses. Eur. J. Immunol. 44, 2582–2591 (2014).

    Article  PubMed  CAS  Google Scholar 

  164. Nair, R. R., Sinha, P., Khanna, A. & Singh, K. Reduced myeloid-derived suppressor cells in the blood and endometrium is associated with early miscarriage. Am. J. Reprod. Immunol. 73, 479–486 (2015).

    Article  CAS  PubMed  Google Scholar 

  165. Kim, Y. J. et al. Reduced L-arginine level and decreased placental eNOS activity in preeclampsia. Placenta 27, 438–444 (2006).

    Article  CAS  PubMed  Google Scholar 

  166. Zhang, Y. et al. Human trophoblast cells induced MDSCs from peripheral blood CD14+ myelomonocytic cells via elevated levels of CCL2. Cell. Mol. Immunol. 13, 615–627 (2016).

    Article  CAS  PubMed  Google Scholar 

  167. Gervassi, A. et al. Myeloid derived suppressor cells are present at high frequency in neonates and suppress in vitro T cell responses. PLoS One 9, e107816 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. Rieber, N. et al. Neutrophilic myeloid-derived suppressor cells in cord blood modulate innate and adaptive immune responses. Clin. Exp. Immunol. 174, 45–52 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Köstlin, N. et al. Granulocytic myeloid-derived suppressor cells from human cord blood modulate T-helper cell response towards an anti-inflammatory phenotype. Immunology 152, 89–101 (2017).

    Article  PubMed  CAS  Google Scholar 

  170. Leiber, A. et al. Neonatal myeloid derived suppressor cells show reduced apoptosis and immunosuppressive activity upon infection with Escherichia coli. Eur. J. Immunol. 47, 1009–1021 (2017).

    Article  CAS  PubMed  Google Scholar 

  171. Heinemann, A. S. et al. In neonates S100A8/S100A9 alarmins prevent the expansion of a specific inflammatory monocyte population promoting septic shock. FASEB J. 31, 1153–1164 (2017).

    Article  CAS  PubMed  Google Scholar 

  172. Ulas, T. et al. S100-alarmin-induced innate immune programming protects newborn infants from sepsis. Nat. Immunol. 18, 622–632 (2017).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the US National Institutes of Health (grants CA084488 and CA100062 to D.G.). We thank R. Kim for help with the preparation of the manuscript.

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Veglia, F., Perego, M. & Gabrilovich, D. Myeloid-derived suppressor cells coming of age. Nat Immunol 19, 108–119 (2018). https://doi.org/10.1038/s41590-017-0022-x

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