Skip to main content
SpringerLink
Log in

Myeloid-Derived Suppressor Cells in Cancer

  • Chapter
  • First Online:
Innate Immune Regulation and Cancer Immunotherapy

  • 1808 Accesses

Abstract

Accumulation of suppressive leukocytes is the hallmark of several pathological conditions, including tumors. Among these leukocytes, myeloid-derived suppressor cells (MDSCs) are thought to play a major role in regulating antitumor immunity. MDSCs encompass a heterogeneous population characterized by its myeloid origin and ability to suppress T-cell responses. The suppressive activity of these cells has been shown to be both dependent and independent on l-arginine metabolism. In this chapter, we describe and address the complex role of MDSCs in cancer, including their origin, phenotype, interaction in other immune regulatory networks, and mechanisms they use to exert their suppressive activity. Furthermore, we discuss the possibilities to convert the suppressive nature of these cells and combine this approach with immunotherapy in order to enhance therapeutic gain in cancer.

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

  • Almand B, Clark JI et al (2001) Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol 166(1):678–689

    PubMed  CAS  Google Scholar 

  • Badn W, Hegardt P et al (2007a) Inhibition of inducible nitric oxide synthase enhances anti-tumour immune responses in rats immunized with IFN-gamma-secreting glioma cells. Scand J Immunol 65(3):289–297

    Article  PubMed  CAS  Google Scholar 

  • Badn W, Visse E et al (2007b) Postimmunization with IFN-gamma-secreting glioma cells ­combined with the inducible nitric oxide synthase inhibitor mercaptoethylguanidine prolongs survival of rats with intracerebral tumors. J Immunol 179(6):4231–4238

    PubMed  CAS  Google Scholar 

  • Bentz BG, Haines GK 3rd et al (2000) Increased protein nitrosylation in head and neck squamous cell carcinogenesis. Head Neck 22(1):64–70

    Article  PubMed  CAS  Google Scholar 

  • Brito C, Naviliat M et al (1999) Peroxynitrite inhibits T lymphocyte activation and proliferation by promoting impairment of tyrosine phosphorylation and peroxynitrite-driven apoptotic death. J Immunol 162(6):3356–3366

    PubMed  CAS  Google Scholar 

  • Bronte V, Apolloni E et al (2000) Identification of a CD11b(+)/Gr-1(+)/CD31(+) myeloid progenitor capable of activating or suppressing CD8(+) T cells. Blood 96(12):3838–3846

    PubMed  CAS  Google Scholar 

  • Bronte V, Mocellin S (2009) Suppressive influences in the immune response to cancer. J Immunother 32(1):1–11

    Article  PubMed  Google Scholar 

  • Bronte V, Serafini P et al (2003) IL-4-induced arginase 1 suppresses alloreactive T cells in tumor-bearing mice. J Immunol 170(1):270–278

    PubMed  CAS  Google Scholar 

  • Bronte V, Wang M et al (1998) Apoptotic death of CD8+ T lymphocytes after immunization: induction of a suppressive population of Mac-1+/Gr-1+ cells. J Immunol 161(10):5313–5320

    PubMed  CAS  Google Scholar 

  • Bronte V, Zanovello P (2005) Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol 5(8):641–654

    Article  PubMed  CAS  Google Scholar 

  • Corzo CA, Cotter MJ et al (2009) Mechanism regulating reactive oxygen species in tumor-induced myeloid-derived suppressor cells. J Immunol 182(9):5693–5701

    Article  PubMed  CAS  Google Scholar 

  • Dannenberg AJ, Altorki NK et al (2001) Cyclo-oxygenase 2: a pharmacological target for the prevention of cancer. Lancet Oncol 2(9):544–551

    Article  PubMed  CAS  Google Scholar 

  • De Santo C, Serafini P et al (2005) Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination. Proc Natl Acad Sci U S A 102(11):4185–4190

    Article  PubMed  Google Scholar 

  • Diaz-Montero CM, Salem ML 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(1):49–59

    Article  PubMed  CAS  Google Scholar 

  • Dolcetti L, Marigo I et al (2008) Myeloid-derived suppressor cell role in tumor-related inflammation. Cancer Lett 267(2):216–225

    Article  PubMed  CAS  Google Scholar 

  • Dolcetti L, Peranzoni E et al (2010) Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF. Eur J Immunol 40(1):22–35

    Article  PubMed  CAS  Google Scholar 

  • Donkor MK, Lahue E et al (2009) Mammary tumor heterogeneity in the expansion of myeloid-derived suppressor cells. Int Immunopharmacol 9(7–8):937–948

    Article  PubMed  CAS  Google Scholar 

  • Dupuis M, De Jesus Ibarra-Sanchez M et al (2003) Gr-1+ myeloid cells lacking T cell protein tyrosine phosphatase inhibit lymphocyte proliferation by an IFN-gamma- and nitric oxide-dependent mechanism. J Immunol 171(2):726–732

    PubMed  CAS  Google Scholar 

  • Ekmekcioglu S, Ellerhorst J et al (2000) Inducible nitric oxide synthase and nitrotyrosine in human metastatic melanoma tumors correlate with poor survival. Clin Cancer Res 6(12):4768–4775

    PubMed  CAS  Google Scholar 

  • Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9(3):162–174

    Article  PubMed  CAS  Google Scholar 

  • Gallina G, Dolcetti L et al (2006) Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells. J Clin Invest 116(10):2777–2790

    Article  PubMed  CAS  Google Scholar 

  • Gasparini G, Longo R et al (2003) Inhibitors of cyclo-oxygenase 2: a new class of anticancer agents? Lancet Oncol 4(10):605–615

    Article  PubMed  CAS  Google Scholar 

  • Henson SE, Nichols TC et al (1999) The ectoenzyme gamma-glutamyl transpeptidase regulates antiproliferative effects of S-nitrosoglutathione on human T and B lymphocytes. J Immunol 163(4):1845–1852

    PubMed  CAS  Google Scholar 

  • Hoechst B, Ormandy LA et al (2008) A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology 135(1):234–243

    Article  PubMed  CAS  Google Scholar 

  • Huang B, Pan PY 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  PubMed  CAS  Google Scholar 

  • Iwasaki H, Akashi K (2007) Myeloid lineage commitment from the hematopoietic stem cell. Immunity 26(6):726–740

    Article  PubMed  CAS  Google Scholar 

  • Junttila IS, Mizukami K et al (2008) Tuning sensitivity to IL-4 and IL-13: differential expression of IL-4Ralpha, IL-13Ralpha1, and gammac regulates relative cytokine sensitivity. J Exp Med 205(11):2595–2608

    Article  PubMed  CAS  Google Scholar 

  • Kortylewski M, Kujawski M et al (2005) Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med 11(12):1314–1321

    Article  PubMed  CAS  Google Scholar 

  • Kujawski M, Kortylewski M et al (2008) Stat3 mediates myeloid cell-dependent tumor angiogenesis in mice. J Clin Invest 118(10):3367–3377

    Article  PubMed  CAS  Google Scholar 

  • Kusmartsev S, Cheng F et al (2003) All-trans-retinoic acid eliminates immature myeloid cells from tumor-bearing mice and improves the effect of vaccination. Cancer Res 63(15):4441–4449

    PubMed  CAS  Google Scholar 

  • Kusmartsev S, Nefedova Y et al (2004) Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species. J Immunol 172(2):989–999

    PubMed  CAS  Google Scholar 

  • Lambeth JD (2004) NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol 4(3):181–189

    Article  PubMed  CAS  Google Scholar 

  • Li Q, Pan PY et al (2004) Role of immature myeloid Gr-1+ cells in the development of antitumor immunity. Cancer Res 64(3):1130–1139

    Article  PubMed  CAS  Google Scholar 

  • Mandruzzato S, Solito S et al (2009) IL4Ralpha+ myeloid-derived suppressor cell expansion in cancer patients. J Immunol 182(10):6562–6568

    Article  PubMed  CAS  Google Scholar 

  • Mantovani G, Maccio A et al (2003) Antioxidant agents are effective in inducing lymphocyte progression through cell cycle in advanced cancer patients: assessment of the most important laboratory indexes of cachexia and oxidative stress. J Mol Med 81(10):664–673

    Article  PubMed  CAS  Google Scholar 

  • Marigo I, Bosio E et al (2010) Tumor-induced tolerance and immune suppression depend on the C/EBPbeta transcription factor. Immunity 32(6):790–802

    Article  PubMed  CAS  Google Scholar 

  • Mazzoni A, Bronte V et al (2002) Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism. J Immunol 168(2):689–695

    PubMed  CAS  Google Scholar 

  • Movahedi K, Guilliams M et al (2008) Identification of discrete tumor-induced myeloid-derived ­suppressor cell subpopulations with distinct T cell-suppressive activity. Blood 111(8):4233–4244

    Article  PubMed  CAS  Google Scholar 

  • Nagaraj S, Gupta K et al (2007) Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat Med 13(7):828–835

    Article  PubMed  CAS  Google Scholar 

  • Nefedova Y, Huang M et al (2004) Hyperactivation of STAT3 is involved in abnormal differentiation of dendritic cells in cancer. J Immunol 172(1):464–474

    PubMed  CAS  Google Scholar 

  • Otsuji M, Kimura Y et al (1996) Oxidative stress by tumor-derived macrophages suppresses the expression of CD3 zeta chain of T-cell receptor complex and antigen-specific T-cell responses. Proc Natl Acad Sci U S A 93(23):13119–13124

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez PC, Ernstoff MS et al (2009) Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes. Cancer Res 69(4):1553–1560

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez PC, Hernandez CP et al (2005) Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma. J Exp Med 202(7):931–939

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez PC, Ochoa AC (2008) Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives. Immunol Rev 222:180–191

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez PC, Quiceno DG 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(16):5839–5849

    Article  PubMed  CAS  Google Scholar 

  • Rutschman R, Lang R et al (2001) Cutting edge: Stat6-dependent substrate depletion regulates nitric oxide production. J Immunol 166(4):2173–2177

    PubMed  CAS  Google Scholar 

  • Sawanobori Y, Ueha S et al (2008) Chemokine-mediated rapid turnover of myeloid-derived suppressor cells in tumor-bearing mice. Blood 111(12):5457–5466

    Article  PubMed  CAS  Google Scholar 

  • Serafini P, Borrello I et al (2006) Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. Semin Cancer Biol 16(1):53–65

    Article  PubMed  CAS  Google Scholar 

  • Serafini P, Mgebroff S et al (2008) Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells. Cancer Res 68(13):5439–5449

    Article  PubMed  CAS  Google Scholar 

  • Sharma S, Yang SC et al (2005a) Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+ CD25+ T regulatory cell activities in lung cancer. Cancer Res 65(12):5211–5220

    Article  PubMed  CAS  Google Scholar 

  • Sharma S, Zhu L et al (2005b) Cyclooxygenase 2 inhibition promotes IFN-gamma-dependent enhancement of antitumor responses. J Immunol 175(2):813–819

    PubMed  CAS  Google Scholar 

  • Shojaei F, Wu X et al (2007) Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature 450(7171):825–831

    Article  PubMed  CAS  Google Scholar 

  • Sica A, Bronte V (2007) Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest 117(5):1155–1166

    Article  PubMed  CAS  Google Scholar 

  • Sinha P, Clements VK et al (2005) Interleukin-13-regulated M2 macrophages in combination with myeloid suppressor cells block immune surveillance against metastasis. Cancer Res 65(24):11743–11751

    Article  PubMed  CAS  Google Scholar 

  • Stolina M, Sharma S et al (2000) Specific inhibition of cyclooxygenase 2 restores antitumor reactivity by altering the balance of IL-10 and IL-12 synthesis. J Immunol 164(1):361–370

    PubMed  CAS  Google Scholar 

  • Szabo C, Ischiropoulos H et al (2007) Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nat Rev Drug Discov 6(8):662–680

    Article  PubMed  CAS  Google Scholar 

  • Szuster-Ciesielska A, Hryciuk-Umer E et al (2004) Reactive oxygen species production by blood neutrophils of patients with laryngeal carcinoma and antioxidative enzyme activity in their blood. Acta Oncol 43(3):252–258

    Article  PubMed  CAS  Google Scholar 

  • Talmadge JE (2007) Pathways mediating the expansion and immunosuppressive activity of myeloid-derived suppressor cells and their relevance to cancer therapy. Clin Cancer Res 13(18 Pt 1):5243–5248

    Article  PubMed  CAS  Google Scholar 

  • Terabe M, Matsui S et al (2000) NKT cell-mediated repression of tumor immunosurveillance by IL-13 and the IL-4R-STAT6 pathway. Nat Immunol 1(6):515–520

    Article  PubMed  CAS  Google Scholar 

  • Terabe M, Matsui S et al (2003) Transforming growth factor-beta production and myeloid cells are an effector mechanism through which CD1d-restricted T cells block cytotoxic T lymphocyte-mediated tumor immunosurveillance: abrogation prevents tumor recurrence. J Exp Med 198(11):1741–1752

    Article  PubMed  CAS  Google Scholar 

  • Wang HY, Wang RF (2007) Regulatory T cells and cancer. Curr Opin Immunol 19(2):217–223

    Article  PubMed  CAS  Google Scholar 

  • Youn JI, Nagaraj S et al (2008) Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J Immunol 181(8):5791–5802

    PubMed  CAS  Google Scholar 

  • Zou W (2005) Immunosuppressive networks in the tumour environment and their therapeutic ­relevance. Nat Rev Cancer 5(4):263–274

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the Italian Ministry of Health, Fondazione Cassa di Risparmio di Padova e Rovigo, Italian Association for Cancer Research (AIRC), Progetto Locale SUN 2008, Istituto Superiore Sanità -Alleanza Contro il Cancro (project no. ACC8), and Swedish Research Council (Vetenskapsrådet, VR).

Author information

Authors and Affiliations

  1. Istituto Oncologico Veneto, Via Gattamelata 64, 35128, Padova, Italy

    Wiaam Badn & Vincenzo Bronte

Authors
  1. Wiaam Badn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vincenzo Bronte
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vincenzo Bronte .

Editor information

Editors and Affiliations

  1. Center for Cell & Gene Therapy, Baylor College of Medicine, Baylor Plaza 1, Houston, 77030, Texas, USA

    Rongfu Wang

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Badn, W., Bronte, V. (2012). Myeloid-Derived Suppressor Cells in Cancer. In: Wang, R. (eds) Innate Immune Regulation and Cancer Immunotherapy. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-9914-6_12

Download citation

Publish with us

Policies and ethics

Search

Navigation