Skip to main content
SpringerLink
Log in

Myeloid-Derived Suppressor Cells in the Tumor Microenvironment

  • Chapter
  • First Online:
Tumor Microenvironment

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1224))

Abstract

Myeloid-derived suppressor cells (MDSCs) represent a heterogenous population of immature myeloid cells capable of modulating immune responses. In the context of cancer, MDSCs are abnormally produced and recruited to the tumor microenvironment (TME) to aid in the establishment of an immunosuppressive TME that facilitates tumor escape. Additionally, MDSCs contribute to non-immunologic aspects of tumor biology, including tumor angiogenesis and metastasis. The clinical significance of MDSCs has recently been appreciated as numerous studies have suggested a correlation between circulating and intratumoral MDSC frequencies and tumor stage, progression, and treatment resistance. In this chapter, we review MDSC characterization, development, expansion, and mechanisms that facilitate immunosuppression and tumor progression. Furthermore, we highlight studies demonstrating the clinical significance of MDSCs in various disease states in addition to strategies that modulate various aspects of MDSC biology for therapeutic gain.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9:162–174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Khaled YS, Ammori BJ, Elkord E (2013) Myeloid-derived suppressor cells in cancer: recent progress and prospects. Immunol Cell Biol 91:493–502

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  4. Blidner AG et al (2015) Differential response of myeloid-derived suppressor cells to the nonsteroidal anti-inflammatory agent indomethacin in tumor-associated and tumor-free microenvironments. J Clin Invest 194:3452–3462

    CAS  Google Scholar 

  5. Waigel S et al (2016) MIF inhibition reverts the gene expression profile of human melanoma cell line-induced MDSCs to normal monocytes. Genomics Data 7:240–242

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Serafini P, Borrello I, Bronte V (2006) Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. Semin Cancer Biol 16:53–65

    Article  CAS  PubMed  Google Scholar 

  8. Dolcetti L et al (2009) Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF. Eur J Immunol 40:22–35

    Article  CAS  Google Scholar 

  9. Youn J-I, Nagaraj S, Collazo M, Gabrilovich DI (2008) Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J Immunol 181:5791–5802

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. Haile LA, Gamrekelashvili J, Manns MP, Korangy F, Greten TF (2010) CD49d is a new marker for distinct myeloid-derived suppressor cell subpopulations in mice. J Immunol 185:203–210

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Youn J-I, Collazo M, Shalova IN, Biswas SK, Gabrilovich DI (2012) Characterization of the nature of granulocytic myeloid-derived suppressor cells in tumor-bearing mice. J Leukoc Biol 91:167–181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  16. Damuzzo V et al (2015) Complexity and challenges in defining myeloid-derived suppressor cells. Cytom B Clin Cytom 88:77–91

    Article  CAS  Google Scholar 

  17. Wynn TA, Chawla A, Pollard JW (2013) Macrophage biology in development, homeostasis and disease. Nature 496:445–455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Movahedi K et al (2010) Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res 70:5728–5739

    Article  CAS  PubMed  Google Scholar 

  19. Franklin RA et al (2014) The cellular and molecular origin of tumor-associated macrophages. Science 344:921–925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Corzo CA et al (2010) HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med 207:2439–2453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Elliott LA, Doherty GA, Sheahan K, Ryan EJ (2017) Human tumor-infiltrating myeloid cells: phenotypic and functional diversity. Front Immunol 8:86

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Giese MA, Hind LE, Huttenlocher A (2019) Neutrophil plasticity in the tumor microenvironment. Blood 133:2159–2167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Coffelt SB, Wellenstein MD, De Visser KE (2016) Neutrophils in cancer: neutral no more. Nat Rev Cancer 16:431–446

    Article  CAS  PubMed  Google Scholar 

  24. Zhou J, Nefedova Y, Lei A, Gabrilovich D (2018) Neutrophils and PMN-MDSC: their biological role and interaction with stromal cells. Semin Immunol 35:19–28

    Article  CAS  PubMed  Google Scholar 

  25. Condamine T et al (2016) Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients. Sci Immunol 1:aaf8943–aaf8943

    Article  PubMed  PubMed Central  Google Scholar 

  26. Gabrilovich DI (2017) Myeloid-derived suppressor cells. Cancer Immunol Res 5:3–8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Messmer MN, Netherby CS, Banik D, Abrams SI (2015) Tumor-induced myeloid dysfunction and its implications for cancer immunotherapy. Cancer Immunol Immunother 64:1–13

    Article  CAS  PubMed  Google Scholar 

  28. Gabrilovich DI et al (2007) The terminology issue for myeloid-derived suppressor cells. Cancer Res 67:425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Condamine T, Mastio J, Gabrilovich DI (2015) Transcriptional regulation of myeloid-derived suppressor cells. J Leukoc Biol 98:913–922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Condamine T, Gabrilovich DI (2011) Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol 32:19–25

    Article  CAS  PubMed  Google Scholar 

  31. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V (2012) Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 12:253–268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ostrand-Rosenberg S, Sinha P (2009) Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 182:4499–4506

    Article  CAS  PubMed  Google Scholar 

  33. Umansky V, Blattner C, Gebhardt C, Utikal J (2016) The role of myeloid-derived suppressor cells (MDSC) in cancer progression. Vaccine 4:36

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  35. Serafini P et al (2004) High-dose granulocyte-macrophage colony-stimulating factor-producing vaccines impair the immune response through the recruitment of myeloid suppressor cells. Cancer Res 64:6337–6343

    Article  CAS  PubMed  Google Scholar 

  36. Lechner MG, Liebertz DJ, Epstein AL (2010) Characterization of cytokine-induced myeloid-derived suppressor cells from normal human peripheral blood mononuclear cells. J Immunol 185:2273–2284

    Article  CAS  PubMed  Google Scholar 

  37. Lutz MB et al (2000) Immature dendritic cells generated with low doses of GM-CSF in the absence of IL-4 are maturation resistant and prolong allograft survival in vivo. Eur J Immunol 30:1813–1822

    Article  CAS  PubMed  Google Scholar 

  38. Bayne LJ et al (2012) Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 21:822–835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Morales JK, Kmieciak M, Knutson KL, Bear HD, Manjili MH (2010) GM-CSF is one of the main breast tumor-derived soluble factors involved in the differentiation of CD11b-Gr1- bone marrow progenitor cells into myeloid-derived suppressor cells. Breast Cancer Res Treat 123:39–49

    Article  CAS  PubMed  Google Scholar 

  40. Bronte V et al (2015) 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. https://doi.org/10.4049/jimmunol.1501103

    Article  CAS  Google Scholar 

  41. Parmiani G et al (2006) Opposite immune functions of GM-CSF administered as vaccine adjuvant in cancer patients. Ann Oncol 18:226–232

    Article  PubMed  Google Scholar 

  42. Gabrilovich DI et al (1996) Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 2:1096–1103

    Article  CAS  PubMed  Google Scholar 

  43. Larrivee B, Pollet I, Karsan A (2005) Activation of vascular endothelial growth factor receptor-2 in bone marrow leads to accumulation of myeloid cells: role of granulocyte-macrophage colony-stimulating factor. J Immunol 175:3015–3024

    Article  CAS  PubMed  Google Scholar 

  44. Horikawa N et al (2017) Expression of vascular endothelial growth factor in ovarian cancer inhibits tumor immunity through the accumulation of myeloid-derived suppressor cells. Clin Cancer Res 23:587–599. https://doi.org/10.1158/1078-0432.ccr-16-0387

    Article  CAS  PubMed  Google Scholar 

  45. Bunt SK, Sinha P, Clements VK, Leips J, Ostrand-Rosenberg S (2006) Inflammation induces myeloid-derived suppressor cells that facilitate tumor progression. J Immunol 176:284–290

    Article  CAS  PubMed  Google Scholar 

  46. Tu S et al (2008) Overexpression of interleukin-1β induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. Cancer Cell 14:408–419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Elkabets M et al (2010) IL-1β regulates a novel myeloid-derived suppressor cell subset that impairs NK cell development and function. Eur J Immunol 40:3347–3357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lewis AM, Varghese S, Xu H, Alexander HR (2006) Interleukin-1 and cancer progression: the emerging role of interleukin-1 receptor antagonist as a novel therapeutic agent in cancer treatment. J Transl Med 4:48

    Article  PubMed  PubMed Central  Google Scholar 

  49. Bunt SK et al (2007) Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression. Cancer Res 67:10019–10026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Wu C-T et al (2012) Significance of IL-6 in the transition of hormone-resistant prostate cancer and the induction of myeloid-derived suppressor cells. J Mol Med 90:1343–1355

    Article  CAS  PubMed  Google Scholar 

  51. Sumida K et al (2012) Anti-IL-6 receptor mAb eliminates myeloid-derived suppressor cells and inhibits tumor growth by enhancing T-cell responses. Eur J Immunol 42:2060–2072

    Article  CAS  PubMed  Google Scholar 

  52. Dufait I et al (2016) Signal transducer and activator of transcription 3 in myeloid-derived suppressor cells: an opportunity for cancer therapy. Oncotarget 7:42698–42715. https://doi.org/10.18632/oncotarget.8311

    Article  PubMed  PubMed Central  Google Scholar 

  53. De Veirman K et al (2015) Multiple myeloma induces Mcl-1 expression and survival of myeloid-derived suppressor cells. Oncotarget 6:10532–10547

    Article  PubMed  PubMed Central  Google Scholar 

  54. Cheng P et al (2008) Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J Exp Med 205:2235–2249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Waight JD et al (2013) Myeloid-derived suppressor cell development is regulated by a STAT/IRF-8 axis. J Clin Invest 123:4464–4478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Pal R et al (2009) C/EBP regulates transcription factors critical for proliferation and survival of multiple myeloma cells. Blood 114:3890–3898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Zhang H et al (2010) STAT3 controls myeloid progenitor growth during emergency granulopoiesis. Blood 116:2462–2471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Mackert J et al (2017) Dual negative roles of C/EBPα in the expansion and pro-tumor functions of MDSCs. Sci Rep 7:14048

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Peng Y, Croce CM (2016) The role of MicroRNAs in human cancer. Signal Transduct Target Ther 1:15004

    Article  PubMed  PubMed Central  Google Scholar 

  60. Baltimore D, Boldin MP, O’Connell RM, Rao DS, Taganov KD (2008) MicroRNAs: new regulators of immune cell development and function. Nat Immunol 9:839–845

    Article  CAS  PubMed  Google Scholar 

  61. Li L et al (2014) MicroRNA-155 and MicroRNA-21 promote the expansion of functional myeloid-derived suppressor cells. J Immunol 192:1034–1043

    Article  CAS  PubMed  Google Scholar 

  62. Bunt SK, Clements VK, Hanson EM, Sinha P, Ostrand-Rosenberg S (2009) Inflammation enhances myeloid-derived suppressor cell cross-talk by signaling through Toll-like receptor 4. J Leukoc Biol 85:996–1004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Liu Y et al (2010) Contribution of MyD88 to the tumor exosome-mediated induction of myeloid derived suppressor cells. Am J Pathol 176:2490–2499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Achyut et al (2017) Canonical NFκB signaling in myeloid cells is required for the glioblastoma growth. Sci Rep 7:13754

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  66. Mao Y et al (2014) Inhibition of tumor-derived prostaglandin-E2 blocks the induction of myeloid-derived suppressor cells and recovers natural killer cell activity. Clin Cancer Res 20:4096–4106

    Article  CAS  PubMed  Google Scholar 

  67. Sinha P, Clements VK, Fulton AM, Ostrand-Rosenberg S (2007) Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res 67:4507–4513

    Article  CAS  PubMed  Google Scholar 

  68. Cubillos-Ruiz JR, Bettigole SE, Glimcher LH (2017) Tumorigenic and immunosuppressive effects of endoplasmic reticulum stress in cancer. Cell 168:692–706

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  70. Condamine T et al (2014) ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R–mediated apoptosis. J Clin Invest 124:2626–2639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Zea AH et al (2004) L-arginine modulates CD3ζ expression and T cell function in activated human T lymphocytes. Cell Immunol 232:21–31

    Article  CAS  PubMed  Google Scholar 

  72. Munder M et al (2006) Suppression of T-cell functions by human granulocyte arginase. Blood 108:1627–1634

    Article  CAS  PubMed  Google Scholar 

  73. Rodriguez PC et al (2004) Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res 64:5839–5849

    Article  CAS  PubMed  Google Scholar 

  74. Srivastava MK, Sinha P, Clements VK, Rodriguez P, Ostrand-Rosenberg S (2010) Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine. Cancer Res 70:68–77

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  76. Otsuji M, Kimura Y, Aoe T, Okamoto Y, Saito T (1996) Oxidative stress by tumor-derived macrophages suppresses the expression of CD3 chain of T-cell receptor complex and antigen-specific T-cell responses. Proc Natl Acad Sci U S A 93:13119–13124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Feng S et al (2018) Myeloid-derived suppressor cells inhibit T cell activation through nitrating LCK in mouse cancers. Proc Natl Acad Sci 115:10094–10099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Molon B et al (2011) Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. J Exp Med 208:1949–1962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Janssens R et al (2018) Peroxynitrite exposure of CXCL12 impairs monocyte, lymphocyte and endothelial cell chemotaxis, lymphocyte extravasation in vivo and anti-HIV-1 activity. Front Immunol 9:1933

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Chaudhary B, Elkord E (2016) Regulatory T cells in the tumor microenvironment and cancer progression: role and therapeutic targeting. Vaccine 4:28

    Article  CAS  Google Scholar 

  81. Ghiringhelli F et al (2005) Tumor cells convert immature myeloid dendritic cells into TGF-β–secreting cells inducing CD4+CD25+ regulatory T cell proliferation. J Exp Med 202:919–929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Huang B et al (2006) Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Res 66:1123–1131

    Article  CAS  PubMed  Google Scholar 

  83. Serafini P, Mgebroff S, Noonan K, Borrello I (2008) Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells. Cancer Res 68:5439–5449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Hoechst B, Gamrekelashvili J, Manns MP, Greten TF, Korangy F (2011) Plasticity of human Th17 cells and iTregs is orchestrated by different subsets of myeloid cells. Blood 117:6532–6541

    Article  CAS  PubMed  Google Scholar 

  85. Lee CR et al (2016) Myeloid-derived suppressor cells are controlled by regulatory T cells via TGF-β during murine colitis. Cell Rep 17:3219–3232

    Article  CAS  PubMed  Google Scholar 

  86. Sinha P, Clements VK, Bunt SK, Albelda SM, Ostrand-Rosenberg S (2007) Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J Immunol 179:977–983

    Article  CAS  PubMed  Google Scholar 

  87. Beury DW et al (2014) Cross-talk among myeloid-derived suppressor cells, macrophages, and tumor cells impacts the inflammatory milieu of solid tumors. J Leukoc Biol 96:1109–1118

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Haverkamp JM, Crist SA, Elzey BD, Cimen C, Ratliff TL (2008) In vivo suppressive function of myeloid-derived suppressor cells is limited to the inflammatory site. Bone 23:1–7

    Google Scholar 

  89. Maenhout SK, Van Lint S, Emeagi PU, Thielemans K, Aerts JL (2014) Enhanced suppressive capacity of tumor-infiltrating myeloid-derived suppressor cells compared with their peripheral counterparts. Int J Cancer 134:1077–1090

    Article  CAS  PubMed  Google Scholar 

  90. Hossain F et al (2015) Inhibition of fatty acid oxidation modulates immunosuppressive functions of myeloid-derived suppressor cells and enhances cancer therapies. Cancer Immunol Res 3:1236–1247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Kumar V, Patel S, Tcyganov E, Gabrilovich DI (2016) The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol 37:208–220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Stromnes IM et al (2014) Targeted depletion of an MDSC subset unmasks pancreatic ductal adenocarcinoma to adaptive immunity. Gut 63:1769–1781

    Article  CAS  PubMed  Google Scholar 

  93. Lang S et al (2018) Clinical relevance and suppressive capacity of human myeloid-derived suppressor cell subsets. Clin Cancer Res 24:4834–4844

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Yamauchi Y et al (2018) Circulating and tumor myeloid-derived suppressor cells in resectable non-small cell lung cancer. Am J Respir Crit Care Med 198:777–787

    Article  PubMed  Google Scholar 

  96. Safarzadeh E et al (2019) Circulating myeloid-derived suppressor cells: an independent prognostic factor in patients with breast cancer. J Cell Physiol 234:3515–3525

    Article  CAS  PubMed  Google Scholar 

  97. Nishida N, Yano H, Nishida T, Kamura T, Kojiro M (2006) Angiogenesis in cancer. Vasc Health Risk Manag 2:213–219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Yang L et al (2004) Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 6:409–421

    Article  CAS  PubMed  Google Scholar 

  99. Du R et al (2008) HIF1α induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13:206–220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Binsfeld M et al (2016) Granulocytic myeloid-derived suppressor cells angiogenesis in the context of multiple myeloma promote. Oncotarget 7:37931–37943

    Article  PubMed  PubMed Central  Google Scholar 

  101. Parihar R et al (2019) NK cells expressing a chimeric activating receptor eliminate MDSCs and rescue impaired CAR-T cell activity against solid tumors. Cancer Immunol Res 7:363–376. https://doi.org/10.1158/2326-6066.CIR-18-0572

    Article  PubMed  PubMed Central  Google Scholar 

  102. Lecouter J et al (2003) The endocrine-gland-derived VEGF homologue Bv8 promotes angiogenesis in the testis: localization of Bv8 receptors to endothelial cells. Proc Natl Acad Sci 100:2685–2690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Shojaei F et al (2007) Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature 450:825–831

    Article  CAS  PubMed  Google Scholar 

  104. Shojaei F, Singh M, Thompson JD, Ferrara N (2008) Role of Bv8 in neutrophil-dependent angiogenesis in a transgenic model of cancer progression. Proc Natl Acad Sci 105:2640–2645

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Yu J et al (2013) Myeloid-derived suppressor cells suppress antitumor immune responses through IDO expression and correlate with lymph node metastasis in patients with breast cancer. J Immunol 190:3783–3797

    Article  CAS  PubMed  Google Scholar 

  106. Huang A et al (2013) 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

    Article  CAS  PubMed  Google Scholar 

  107. Weide B et al (2014) Myeloid-derived suppressor cells predict survival of patients with advanced melanoma: comparison with regulatory T cells and NY-ESO-1- or melan-A-specific T cells. Clin Cancer Res 20:1601–1609

    Article  CAS  PubMed  Google Scholar 

  108. Hossain DMS et al (2015) TLR9-targeted STAT3 silencing abrogates immunosuppressive activity of myeloid-derived suppressor cells from prostate cancer patients. Clin Cancer Res 21:3771–3782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Clark CE et al (2007) Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res 67:9518–9527

    Article  CAS  PubMed  Google Scholar 

  110. Wang Y, Ding Y, Guo N, Wang S (2019) MDSCs: key criminals of tumor pre-metastatic niche formation. Front Immunol 10:172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Kitamura T, Qian B-Z, Pollard JW (2015) Immune cell promotion of metastasis. Nat Rev Immunol 15:73–86

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Liu Y, Cao X (2016) Characteristics and significance of the pre-metastatic niche. Cancer Cell 30:668–681

    Article  CAS  PubMed  Google Scholar 

  113. Wang D, Sun H, Wei J, Cen B, Dubois RN (2017) CXCL1 is critical for premetastatic niche formation and metastasis in colorectal cancer. Cancer Res 77:3655–3665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Sceneay J, Parker BS, Smyth MJ, Möller A (2013) Hypoxia-driven immunosuppression contributes to the pre-metastatic niche. Oncoimmunology 2:e22355

    Article  PubMed  PubMed Central  Google Scholar 

  115. Shvedova AA et al (2015) MDSC and TGF are required for facilitation of tumor growth in the lungs of mice exposed to carbon nanotubes. Cancer Res 75:1615–1623

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Shojaei F et al (2009) G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models. Proc Natl Acad Sci 106:6742–6747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Ichikawa M, Williams R, Wang L, Vogl T, Srikrishna G (2011) S100A8/A9 activate key genes and pathways in colon tumor progression. Mol Cancer Res 9:133–148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  119. Ai L et al (2018) Prognostic role of myeloid-derived suppressor cells in cancers: a systematic review and meta-analysis. BMC Cancer 18:1220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Schadendorf D et al (2015) Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 33:1889–1894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Meyer C et al (2014) Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab. Cancer Immunol Immunother 63:247–257

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Gebhardt C et al (2015) Myeloid cells and related chronic inflammatory factors as novel predictive markers in melanoma treatment with ipilimumab. Clin Cancer Res 21:5453–5459

    Article  CAS  PubMed  Google Scholar 

  124. Sade-Feldman M et al (2016) 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

    Article  CAS  PubMed  Google Scholar 

  125. Santegoets SJ et al (2014) Myeloid derived suppressor and dendritic cell subsets are related to clinical outcome in prostate cancer patients treated with prostate GVAX and ipilimumab. J Immunother Cancer 2:31

    Article  PubMed  PubMed Central  Google Scholar 

  126. Liu Y et al (2018) Targeting myeloid-derived suppressor cells for cancer immunotherapy. Cancer Immunol Immunother 67:1181–1195. https://doi.org/10.1007/s00262-018-2175-3

    Article  CAS  PubMed  Google Scholar 

  127. Faivre S, Demetri G, Sargent W, Raymond E (2007) Molecular basis for sunitinib efficacy and future clinical development. Nat Rev Drug Discov 6:734–745

    Article  CAS  PubMed  Google Scholar 

  128. Ko JS et al (2010) Direct and differential suppression of myeloid-derived suppressor cell subsets by sunitinib is compartmentally constrained. Cancer Res 70:3526–3536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Xin H et al (2009) Sunitinib inhibition of Stat3 induces renal cell carcinoma tumor cell apoptosis and reduces immunosuppressive cells. Cancer Res 69:2506–2513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Guislain A et al (2015) Sunitinib pretreatment improves tumor-infiltrating lymphocyte expansion by reduction in intratumoral content of myeloid-derived suppressor cells in human renal cell carcinoma. Cancer Immunol Immunother 64:1241–1250

    Article  CAS  PubMed  Google Scholar 

  131. Kusmartsev S et al (2008) Oxidative stress regulates expression of VEGFR1 in myeloid cells: link to tumor-induced immune suppression in renal cell carcinoma. J Immunol 181:346–353

    Article  CAS  PubMed  Google Scholar 

  132. Limagne E et al (2016) Accumulation of MDSC and Th17 cells in patients with metastatic colorectal cancer predicts the efficacy of a FOLFOX–bevacizumab drug treatment regimen. Cancer Res 76:5241–5252

    Article  CAS  PubMed  Google Scholar 

  133. Kortylewski M et al (2009) In vivo delivery of siRNA to immune cells by conjugation to a TLR9 agonist enhances antitumor immune responses. Nat Biotechnol 27:925–932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Veltman JD et al (2010) COX-2 inhibition improves immunotherapy and is associated with decreased numbers of myeloid-derived suppressor cells in mesothelioma. Celecoxib influences MDSC function. BMC Cancer 10:464

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Fujita M et al (2011) COX-2 blockade suppresses gliomagenesis by inhibiting myeloid-derived suppressor cells. Cancer Res 71:2664–2674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Katoh H et al (2013) CXCR2-expressing myeloid-derived suppressor cells are essential to promote colitis-associated tumorigenesis. Cancer Cell 24:631–644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Najjar YG et al (2017) Myeloid-derived suppressor cell subset accumulation in renal cell carcinoma parenchyma is associated with intratumoral expression of IL1β, IL8, CXCL5, and Mip-1α. Clin Cancer Res 23:2346–2355

    Article  CAS  PubMed  Google Scholar 

  138. Zhu H et al (2017) CXCR2+ MDSCs promote breast cancer progression by inducing EMT and activated T cell exhaustion. Oncotarget 8:114554–114567

    PubMed  PubMed Central  Google Scholar 

  139. Highfill SL et al (2014) Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. Sci Transl Med 6:237ra67–237ra67

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Sun L et al (2019) Inhibiting myeloid-derived suppressor cell trafficking enhances T cell immunotherapy. JCI Insight 4:126853

    Article  PubMed  Google Scholar 

  141. Blattner C et al (2018) CCR5+ myeloid-derived suppressor cells are enriched and activated in melanoma lesions. Cancer Res 78:157–167

    Article  CAS  PubMed  Google Scholar 

  142. Hawila E et al (2017) CCR5 directs the mobilization of CD11b+Gr1+Ly6Clow polymorphonuclear myeloid cells from the bone marrow to the blood to support tumor development. Cell Rep 21:2212–2222

    Article  CAS  PubMed  Google Scholar 

  143. Warrell RP et al (1991) Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl J Med 324:1385–1393

    Article  PubMed  Google Scholar 

  144. Almand B et al (2001) Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol 166:678–689

    Article  CAS  PubMed  Google Scholar 

  145. Gabrilovich DI, Velders MP, Sotomayor EM, Kast WM (2001) Mechanism of immune dysfunction in cancer mediated by immature gr-1+ myeloid cells. J Immunol 166:5398–5406

    Article  CAS  PubMed  Google Scholar 

  146. Nefedova Y et al (2007) Mechanism of all-trans retinoic acid effect on tumor-associated myeloid-derived suppressor cells. Cancer Res 67:11021–11028

    Article  CAS  PubMed  Google Scholar 

  147. Tobin RP et al (2018) Targeting myeloid-derived suppressor cells using all-trans retinoic acid in melanoma patients treated with Ipilimumab. Int Immunopharmacol 63:282–291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Bauer R et al (2018) Blockade of myeloid-derived suppressor cell expansion with all-trans retinoic acid increases the efficacy of anti-angiogenic therapy. Cancer Res 78:3220–3232. https://doi.org/10.1158/0008-5472.can-17-3415

    Article  CAS  PubMed  Google Scholar 

  149. Fleming V et al (2018) Targeting myeloid-derived suppressor cells to bypass tumor-induced immunosuppression. Front Immunol 9:398

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Garrity T et al (1997) Increased presence of CD34+ cells in the peripheral blood of head and neck cancer patients and their differentiation into dendritic cells. Int Immunopharmacol 73:663–669

    CAS  Google Scholar 

  151. Kulbersh JS, Day TA, Gillespie MB, Young MRI (2009) 1α,25-Dihydroxyvitamin D3 to skew intratumoral levels of immune inhibitory CD34+ progenitor cells into dendritic cells. Otolaryngol Head Neck Surg 140:235–240

    Article  PubMed  PubMed Central  Google Scholar 

  152. Walsh JE, Clark A-M, Day TA, Gillespie MB, Young MRI (2010) Use of α,25-Dihydroxyvitamin D3 treatment to stimulate immune infiltration into head and neck squamous cell carcinoma. Hum Immunol 71:659–665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Bruns H et al (2017) CLL-cell-mediated MDSC induction by exosomal miR-155 transfer is disrupted by vitamin D. Leukemia 31:985–988

    Article  CAS  PubMed  Google Scholar 

  154. Serafini P et al (2006) Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med 203:2691–2702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Lin S et al (2017) Phosphodiesterase-5 inhibition suppresses colonic inflammation-induced tumorigenesis via blocking the recruitment of MDSC. Am J Cancer Res 7:41–52

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Meyer C et al (2011) Chronic inflammation promotes myeloid-derived suppressor cell activation blocking antitumor immunity in transgenic mouse melanoma model. Proc Natl Acad Sci U S A 108:17111–17116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Califano JA et al (2015) Tadalafil augments tumor specific immunity in patients with head and neck squamous cell carcinoma. Clin Cancer Res 21:30–38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Weed DT et al (2015) Tadalafil reduces myeloid-derived suppressor cells and regulatory T cells and promotes tumor immunity in patients with head and neck squamous cell carcinoma. Clin Cancer Res 21:39–48

    Article  CAS  PubMed  Google Scholar 

  159. Hassel JC et al (2017) Tadalafil has biologic activity in human melanoma. Results of a pilot trial with Tadalafil in patients with metastatic Melanoma (TaMe). Oncoimmunology 6:e1326440. https://doi.org/10.1080/2162402x.2017.1326440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Huang X, Cui S, Shu Y (2016) Cisplatin selectively downregulated the frequency and immunoinhibitory function of myeloid-derived suppressor cells in a murine B16 melanoma model. Immunol Res 64:160–170

    Article  CAS  PubMed  Google Scholar 

  161. Vincent J et al (2010) 5-fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res 70:3052–3061

    Article  CAS  PubMed  Google Scholar 

  162. Sawant A et al (2013) Enhancement of antitumor immunity in lung cancer by targeting myeloid-derived suppressor cell pathways. Cancer Res 73:6609–6620

    Article  CAS  PubMed  Google Scholar 

  163. Kim N-R, Kim Y-J (2019) Oxaliplatin regulates myeloid-derived suppressor cell-mediated immunosuppression via downregulation of nuclear factor-κB signaling. Cancer Med 8:276–288

    Article  CAS  PubMed  Google Scholar 

  164. Pencheva N, Buss CG, Posada J, Merghoub T, Tavazoie SF (2014) Broad-spectrum therapeutic suppression of metastatic melanoma through nuclear hormone receptor activation. Cell 156:986–1001

    Article  CAS  PubMed  Google Scholar 

  165. Tavazoie MF et al (2018) LXR/ApoE activation restricts innate immune suppression in cancer. Cell 172:825–840.e18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Dasgupta S, Bhattacharya-Chatterjee M, O’Malley BW, Chatterjee SK (2005) Inhibition of NK cell activity through TGF-1 by down-regulation of NKG2D in a murine model of head and neck cancer. J Immunol 175:5541–5550

    Article  CAS  PubMed  Google Scholar 

  167. Boros P, Ochando J, Zeher M (2016) Myeloid derived suppressor cells and autoimmunity. Hum Immunol 77:631–636

    Article  CAS  PubMed  Google Scholar 

  168. Ioannou M et al (2012) Crucial role of granulocytic myeloid-derived suppressor cells in the regulation of central nervous system autoimmune disease. J Immunol 188:1136–1146

    Article  CAS  PubMed  Google Scholar 

  169. Iacobeus E et al (2018) Phenotypic and functional alterations of myeloid-derived suppressor cells during the disease course of multiple sclerosis. Immunol Cell Biol 96:820–830

    Article  CAS  Google Scholar 

  170. Melero-Jerez C et al (2019) The presence and suppressive activity of myeloid-derived suppressor cells are potentiated after interferon-β treatment in a murine model of multiple sclerosis. Neurobiol Dis 127:13–31

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  172. Highfill SL et al (2010) Bone marrow myeloid-derived suppressor cells (MDSCs) inhibit graft-versus-host disease (GVHD) via an arginase-1-dependent mechanism that is up-regulated by interleukin-13. Blood 116:5738–5747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Lv M et al (2015) Monocytic and promyelocytic myeloid-derived suppressor cells may contribute to G-CSF-induced immune tolerance in haplo-identical allogeneic hematopoietic stem cell transplantation. Am J Hematol 90:E9–E16

    Article  CAS  PubMed  Google Scholar 

  174. Dugast A-S et al (2008) Myeloid-derived suppressor cells accumulate in kidney allograft tolerance and specifically suppress effector T cell expansion. J Immunol 180:7898–7906

    Article  CAS  PubMed  Google Scholar 

  175. Zhang W et al (2018) Myeloid-derived suppressor cells in transplantation: the dawn of cell therapy. J Transl Med 16:19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Yang F et al (2019) Adoptive transfer of IFN-γ-induced M-MDSCs promotes immune tolerance to allografts through iNOS pathway. Inflamm Res 68:545–555

    Article  CAS  PubMed  Google Scholar 

  177. Roussel M et al (2017) Mass cytometry deep phenotyping of human mononuclear phagocytes and myeloid-derived suppressor cells from human blood and bone marrow. J Leukoc Biol 102:437–447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Boutté AM, Mcdonald WH, Shyr Y, Yang L, Lin PC (2011) Characterization of the MDSC proteome associated with metastatic murine mammary tumors using label-free mass spectrometry and shotgun proteomics. PLoS One 6:e22446

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  179. Koehn BH et al (2015) GVHD-associated, inflammasome-mediated loss of function in adoptively transferred myeloid-derived suppressor cells. Blood 126:1621–1628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Lopez-Yrigoyen M et al (2019) Genetic programming of macrophages generates an in vitro model for the human erythroid island niche. Nat Commun 10:1–11

    Article  Google Scholar 

Download references

Acknowledgement

Conflict of interest: The authors declare no potential conflicts of interest.

Author information

Authors and Affiliations

  1. Translational Biology and Molecular Medicine Graduate Program, Baylor College of Medicine, Houston, TX, USA

    Matthew Dysthe

  2. Center for Cell and Gene Therapy, Texas Children’s Hospital, Houston Methodist Hospital, and Baylor College of Medicine, Houston, TX, USA

    Matthew Dysthe & Robin Parihar

  3. Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

    Robin Parihar

Authors
  1. Matthew Dysthe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robin Parihar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robin Parihar .

Editor information

Editors and Affiliations

  1. Columbia University Medical Center, Department of Radiology, New York, NY, USA, Federal University of Minas Gerais, Department of Pathology, Belo Horizonte, Minas Gerais, Brazil

    Alexander Birbrair

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Dysthe, M., Parihar, R. (2020). Myeloid-Derived Suppressor Cells in the Tumor Microenvironment. In: Birbrair, A. (eds) Tumor Microenvironment. Advances in Experimental Medicine and Biology, vol 1224. Springer, Cham. https://doi.org/10.1007/978-3-030-35723-8_8

Download citation

Publish with us

Policies and ethics

Search

Navigation