Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Myeloid-derived suppressor cells and their role in pancreatic cancer

Cancer Gene Therapy volume 24, pages 100–105 (2017)Cite this article

Subjects

Abstract

Pancreatic cancer is a devastating disease and ranks as the third most common cause of cancer-related death. Like many cancers, there has been increased interest in the role of the immune system in the progression and development of pancreatic cancer. In particular, immunosuppression within the tumor microenvironment (TME) is thought to impair the host’s antitumor response. In this article, we review myeloid-derived suppressor cells and their contribution to this immunosuppression within the pancreatic TME.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Siegel RL, Miller KD, Jemal A . Cancer statistics, 2015. Cancer J Clin 2015; 65: 5–29.

    Article  Google Scholar 

  2. Zhang Q, Zeng L, Chen Y, Lian G, Qian C, Chen S et al. Pancreatic cancer epidemiology, detection, and management. Gastroenterol Res Pract 2016; 2016: 8962321.

    PubMed  PubMed Central  Google Scholar 

  3. Lee HS, Park SW . Systemic chemotherapy in advanced pancreatic cancer. Gut Liver 2016; 10: 340–347.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997; 15: 2403–2413.

    Article  CAS  Google Scholar 

  5. Kleeff J, Korc M, Apte M, La Vecchia C, Johnson CD, Biankin AV et al. Pancreatic cancer. Nat Rev Dis Primers 2016; 2: 16022.

    Article  Google Scholar 

  6. Hanahan D, Weinberg RA . Hallmarks of cancer: the next generation. Cell 2011; 144: 646–674.

    Article  CAS  Google Scholar 

  7. Nielsen MF, Mortensen MB, Detlefsen S . Key players in pancreatic cancer-stroma interaction: cancer-associated fibroblasts, endothelial and inflammatory cells. World J Gastroenterol 2016; 22: 2678–2700.

    Article  CAS  Google Scholar 

  8. Binenbaum Y, Na'ara S, Gil Z . Gemcitabine resistance in pancreatic ductal adenocarcinoma. Drug Resist Updates: Rev Comment Antimicrob Anticancer Chemother 2015; 23: 55–68.

    Article  Google Scholar 

  9. Waghray M, Yalamanchili M, Dziubinski M, Zeinali M, Erkkinen M, Yang H et al. GM-CSF mediates mesenchymal-epithelial crosstalk in pancreatic cancer. Cancer Discov 2016; 6: 886–899.

    Article  CAS  Google Scholar 

  10. Horioka K, Ohuchida K, Sada M, Zheng B, Moriyama T, Fujita H et al. Suppression of CD51 in pancreatic stellate cells inhibits tumor growth by reducing stroma and altering tumor-stromal interaction in pancreatic cancer. Int J Oncol 2016; 48: 1499–1508.

    Article  CAS  Google Scholar 

  11. Talmadge JE, Gabrilovich DI . History of myeloid-derived suppressor cells. Nat Rev Cancer 2013; 13: 739–752.

    Article  CAS  Google Scholar 

  12. Bergenfelz C, Larsson AM, von Stedingk K, Gruvberger-Saal S, Aaltonen K, Jansson S et al. Systemic monocytic-MDSCs are generated from monocytes and correlate with disease progression in breast cancer patients. PLoS One 2015; 10: e0127028.

    Article  Google Scholar 

  13. Zhang B, Wang Z, Wu L, Zhang M, Li W, Ding J et al. Circulating and tumor-infiltrating myeloid-derived suppressor cells in patients with colorectal carcinoma. PLoS One 2013; 8: e57114.

    Article  CAS  Google Scholar 

  14. Stanojevic I, Miller K, Kandolf-Sekulovic L, Mijuskovic Z, Zolotarevski L, Jovic M et al. A subpopulation that may correspond to granulocytic myeloid-derived suppressor cells reflects the clinical stage and progression of cutaneous melanoma. Int Immunol 2016; 28: 87–97.

    CAS  PubMed  Google Scholar 

  15. Youn JI, Gabrilovich DI . The biology of myeloid-derived suppressor cells: the blessing and the curse of morphological and functional heterogeneity. Eur J Immunol 2010; 40: 2969–2975.

    Article  CAS  Google Scholar 

  16. Bronte V, Brandau S, Chen SH, Colombo MP, Frey AB, Greten TF et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 2016; 7: 12150.

    Article  CAS  Google Scholar 

  17. Zhao Y, Wu T, Shao S, Shi B, Zhao Y . Phenotype, development, and biological function of myeloid-derived suppressor cells. Oncoimmunology 2016; 5: e1004983.

    Article  Google Scholar 

  18. Movahedi K, Guilliams M, Van den Bossche J, Van den Bergh R, Gysemans C, Beschin A et al. Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood 2008; 111: 4233–4244.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  21. Torroella-Kouri M, Rodriguez D, Caso R . Alterations in macrophages and monocytes from tumor-bearing mice: evidence of local and systemic immune impairment. Immunol Res 2013; 57: 86–98.

    Article  CAS  Google Scholar 

  22. Helm O, Mennrich R, Petrick D, Goebel L, Freitag-Wolf S, Roder C et al. Comparative characterization of stroma cells and ductal epithelium in chronic pancreatitis and pancreatic ductal adenocarcinoma. PLoS One 2014; 9: e94357.

    Article  Google Scholar 

  23. Lawrence T, Natoli G . Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol 2011; 11: 750–761.

    Article  CAS  Google Scholar 

  24. Kurahara H, Shinchi H, Mataki Y, Maemura K, Noma H, Kubo F et al. Significance of M2-polarized tumor-associated macrophage in pancreatic cancer. J Surg Res 2011; 167: e211–e219.

    Article  Google Scholar 

  25. Ugel S, De Sanctis F, Mandruzzato S, Bronte V . Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages. J Clin Invest 2015; 125: 3365–3376.

    Article  Google Scholar 

  26. Corzo CA, Condamine T, Lu L, Cotter MJ, Youn JI, Cheng P et al. HIF-1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med 2010; 207: 2439–2453.

    Article  CAS  Google Scholar 

  27. Kumar V, Cheng P, Condamine T, Mony S, Languino LR, McCaffrey JC et al. CD45 phosphatase inhibits STAT3 transcription factor activity in myeloid cells and promotes tumor-associated macrophage differentiation. Immunity 2016; 44: 303–315.

    Article  CAS  Google Scholar 

  28. Narita Y, Wakita D, Ohkur T, Chamoto K, Nishimura T . Potential differentiation of tumor bearing mouse CD11b+Gr-1+ immature myeloid cells into both suppressor macrophages and immunostimulatory dendritic cells. Biomed Res 2009; 30: 7–15.

    Article  CAS  Google Scholar 

  29. Ben-Baruch A . Inflammation-associated immune suppression in cancer: the roles played by cytokines, chemokines and additional mediators. Seminars Cancer Biol 2006; 16: 38–52.

    Article  CAS  Google Scholar 

  30. Mantovani A, Sica A . Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol 2010; 22: 231–237.

    Article  CAS  Google Scholar 

  31. Kurte M, Lopez M, Aguirre A, Escobar A, Aguillon JC, Charo J et al. A synthetic peptide homologous to functional domain of human IL-10 down-regulates expression of MHC class I and transporter associated with antigen processing 1/2 in human melanoma cells. J Immunol 2004; 173: 1731–1737.

    Article  CAS  Google Scholar 

  32. Porembka MR, Mitchem JB, Belt BA, Hsieh CS, Lee HM, Herndon J et al. Pancreatic adenocarcinoma induces bone marrow mobilization of myeloid-derived suppressor cells which promote primary tumor growth. Cancer Immunol Immunother 2012; 61: 1373–1385.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  34. Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ . Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother 2009; 58: 49–59.

    Article  CAS  Google Scholar 

  35. Goedegebuure P, Mitchem JB, Porembka MR, Tan MC, Belt BA, Wang-Gillam A et al. Myeloid-derived suppressor cells: general characteristics and relevance to clinical management of pancreatic cancer. Curr Cancer Drug Targets 2011; 11: 734–751.

    Article  CAS  Google Scholar 

  36. Bayne LJ, Beatty GL, Jhala N, Clark CE, Rhim AD, Stanger BZ et al. Tumor-derived granulocyte-macrophage colony stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 2012; 21: 822–835.

    Article  CAS  Google Scholar 

  37. Pylayeva-Gupta Y, Lee KE, Hajdu CH, Miller G, Bar-Sagi D . Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 2012; 21: 836–847.

    Article  CAS  Google Scholar 

  38. Takeuchi S, Baghdadi M, Tsuchikawa T, Wada H, Nakamura T, Abe H et al. Chemotherapy-derived inflammatory responses accelerate the formation of immunosuppressive myeloid cells in the tissue microenvironment of human pancreatic cancer. Cancer Res 2015; 75: 2629–2640.

    Article  CAS  Google Scholar 

  39. Ko JS, Rayman P, Ireland J, Swaidani S, Li G, Bunting KD et al. Direct and differential suppression of myeloid-derived suppressor cell subsets by sunitinib is compartmentally constrained. Cancer Res 2010; 70: 3526–3536.

    Article  CAS  Google Scholar 

  40. Dolcetti L, Peranzoni E, Ugel S, Marigo I, Fernandez Gomez A, Mesa C et al. Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF. Eur J Immunol 2010; 40: 22–35.

    Article  CAS  Google Scholar 

  41. Hamilton JA . Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol 2008; 8: 533–544.

    Article  CAS  Google Scholar 

  42. Pilon-Thomas S, Nelson N, Vohra N, Jerald M, Pendleton L, Szekeres K et al. Murine pancreatic adenocarcinoma dampens SHIP-1 expression and alters MDSC homeostasis and function. PLoS One 2011; 6: e27729.

    Article  CAS  Google Scholar 

  43. Tu S, Bhagat G, Cui G, Takaishi S, Kurt-Jones EA, Rickman B et al. Overexpression of interleukin-1beta induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. Cancer Cell 2008; 14: 408–419.

    Article  CAS  Google Scholar 

  44. Bunt SK, Yang L, Sinha P, Clements VK, Leips J, Ostrand-Rosenberg S . Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression. Cancer Res 2007; 67: 10019–10026.

    Article  CAS  Google Scholar 

  45. Seifert L, Werba G, Tiwari S, Giao Ly NN, Alothman S, Alqunaibit D et al. The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression. Nature 2016; 532: 245–249.

    Article  CAS  Google Scholar 

  46. Mace TA, Ameen Z, Collins A, Wojcik S, Mair M, Young GS et al. Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner. Cancer Res 2013; 73: 3007–3018.

    Article  CAS  Google Scholar 

  47. Muhlberg L, Kuhnemuth B, Costello E, Shaw V, Sipos B, Huber M et al. miRNA dynamics in tumor-infiltrating myeloid cells modulating tumor progression in pancreatic cancer. Oncoimmunology 2016; 5: e1160181.

    Article  Google Scholar 

  48. Babiak LM, Rybak MJ . Hematological effects associated with beta-lactam use. Drug Intell Clin Pharm 1986; 20: 833–836.

    Article  CAS  Google Scholar 

  49. Kumar V, Gabrilovich DI . Hypoxia-inducible factors in regulation of immune responses in tumour microenvironment. Immunology 2014; 143: 512–519.

    Article  CAS  Google Scholar 

  50. Longo V, Brunetti O, Gnoni A, Cascinu S, Gasparini G, Lorusso V et al. Angiogenesis in pancreatic ductal adenocarcinoma: a controversial issue. Oncotarget 2016 (e-pub ahead of print).

  51. Lunardi S, Muschel RJ, Brunner TB . The stromal compartments in pancreatic cancer: are there any therapeutic targets? Cancer Lett 2014; 343: 147–155.

    Article  CAS  Google Scholar 

  52. Liu G, Bi Y, Shen B, Yang H, Zhang Y, Wang X et al. SIRT1 limits the function and fate of myeloid-derived suppressor cells in tumors by orchestrating HIF-1alpha-dependent glycolysis. Cancer Res 2014; 74: 727–737.

    Article  CAS  Google Scholar 

  53. Huang B, Lei Z, Zhao J, Gong W, Liu J, Chen Z et al. CCL2/CCR2 pathway mediates recruitment of myeloid suppressor cells to cancers. Cancer Lett 2007; 252: 86–92.

    Article  CAS  Google Scholar 

  54. Yang X, Lin Y, Shi Y, Li B, Liu W, Yin W et al. FAP promotes immunosuppression by cancer-associated fibroblasts in the tumor microenvironment via STAT3-CCL2 signaling. Cancer Res 2016; 76: 4124–4135.

    Article  CAS  Google Scholar 

  55. Chang AL, Miska J, Wainwright DA, Dey M, Rivetta CV, Yu D et al. CCL2 produced by the glioma microenvironment is essential for the recruitment of regulatory T cells and myeloid-derived suppressor cells. Cancer Res 2016; 76: 5671–5682.

    Article  CAS  Google Scholar 

  56. Chun E, Lavoie S, Michaud M, Gallini CA, Kim J, Soucy G et al. CCL2 promotes colorectal carcinogenesis by enhancing polymorphonuclear myeloid-derived suppressor cell population and function. Cell Rep 2015; 12: 244–257.

    Article  CAS  Google Scholar 

  57. Hong J, Tobin NP, Rundqvist H, Li T, Lavergne M, GarcĂ­a-IbĂ¡Ă±ez Y et al. Role of tumor pericytes in the recruitment of myeloid-derived suppressor cells. J Natl Cancer Inst 2015; 107: djv209.

    Article  Google Scholar 

  58. Werba G, Seifert L, Miller G . Necroptotic cell death - an unexpected driver of pancreatic oncogenesis. Cell Cycle 2016; 15: 2095–2096.

    Article  CAS  Google Scholar 

  59. Strilic B, Yang L, Albarran-Juarez J, Wachsmuth L, Han K, Muller UC et al. Tumour-cell-induced endothelial cell necroptosis via death receptor 6 promotes metastasis. Nature 2016; 536: 215–218.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  61. Otsuji M, Kimura Y, Aoe T, Okamoto Y, Saito T . 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 USA 1996; 93: 13119–13124.

    Article  CAS  Google Scholar 

  62. Nagaraj S, Gabrilovich DI . Regulation of suppressive function of myeloid-derived suppressor cells by CD4(+) T cells MDSC and CD4(+) T cells. Semin Cancer Biol 2012; 22: 282–288.

    Article  CAS  Google Scholar 

  63. Qu P, Wang LZ, Lin PC . Expansion and functions of myeloid-derived suppressor cells in the tumor microenvironment. Cancer Lett 2016; 380: 253–256.

    Article  CAS  Google Scholar 

  64. Vasquez-Dunddel D, Pan F, Zeng Q, Gorbounov M, Albesiano E, Fu J et al. STAT3 regulates arginase-I in myeloid-derived suppressor cells from cancer patients. J Clin Invest 2013; 123: 1580–1589.

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  66. Haverkamp JM, Smith AM, Weinlich R, Dillon CP, Qualls JE, Neale G et al. Myeloid-derived suppressor activity is mediated by monocytic lineages maintained by continuous inhibition of extrinsic and intrinsic death pathways. Immunity 2014; 41: 947–959.

    Article  CAS  Google Scholar 

  67. Lu B, Yang M, Wang Q . Interleukin-33 in tumorigenesis, tumor immune evasion, and cancer immunotherapy. J Mol Med 2016; 94: 535–543.

    Article  CAS  Google Scholar 

  68. Pinton L, Solito S, Damuzzo V, Francescato S, Pozzuoli A, Berizzi A et al. Activated T cells sustain myeloid-derived suppressor cell-mediated immune suppression. Oncotarget 2016; 7: 1168–1184.

    PubMed  Google Scholar 

  69. Li Y, Li F, Jiang F, Lv X, Zhang R, Lu A et al. A mini-review for cancer immunotherapy: molecular understanding of PD-1/PD-L1 pathway & translational blockade of immune checkpoints. Int J Mol Sci 2016; 17: 1151.

    Article  Google Scholar 

  70. Marigo I, Dolcetti L, Serafini P, Zanovello P, Bronte V . Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells. Immunol Rev 2008; 222: 162–179.

    Article  CAS  Google Scholar 

  71. Yamamoto T, Yanagimoto H, Satoi S, Toyokawa H, Hirooka S, Yamaki S et al. Circulating CD4+CD25+ regulatory T cells in patients with pancreatic cancer. Pancreas 2012; 41: 409–415.

    Article  CAS  Google Scholar 

  72. Lunardi S, Lim SY, Muschel RJ, Brunner TB . IP-10/CXCL10 attracts regulatory T cells: Implication for pancreatic cancer. Oncoimmunology 2015; 4: e1027473.

    Article  Google Scholar 

  73. Huang B, Pan P-Y, Li Q, Sato AI, Levy DE, Bromberg J et al. 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 2006; 66: 1123–1131.

    Article  CAS  Google Scholar 

  74. Viehl CT, Moore TT, Liyanage UK, Frey DM, Ehlers JP, Eberlein TJ et al. Depletion of CD4+CD25+ regulatory T cells promotes a tumor-specific immune response in pancreas cancer-bearing mice. Ann Surg Oncol 2006; 13: 1252–1258.

    Article  Google Scholar 

  75. Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM . Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res 2005; 11: 6713–6721.

    Article  CAS  Google Scholar 

  76. Gurlevik E, Fleischmann-Mundt B, Brooks J, Demir IE, Steiger K, Ribback S et al. Administration of gemcitabine after pancreatic tumor resection in mice induces an antitumor immune response mediated by natural killer cells. Gastroenterology 2016; 151: 338–50.e7.

    Article  Google Scholar 

  77. Meyer C, Sevko A, Ramacher M, Bazhin AV, Falk CS, Osen W et al. Chronic inflammation promotes myeloid-derived suppressor cell activation blocking antitumor immunity in transgenic mouse melanoma model. Proc Natl Acad Sci USA 2011; 108: 17111–17116.

    Article  CAS  Google Scholar 

  78. Karakhanova S, Link J, Heinrich M, Shevchenko I, Yang Y, Hassenpflug M et al. Characterization of myeloid leukocytes and soluble mediators in pancreatic cancer: importance of myeloid-derived suppressor cells. Oncoimmunology 2015; 4: e998519.

    Article  Google Scholar 

  79. Zhu Y, Knolhoff BL, Meyer MA, Nywening TM, West BL, Luo J et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res 2014; 74: 5057–5069.

    Article  CAS  Google Scholar 

  80. Lu P, Yu B, Xu J . Cucurbitacin B regulates immature myeloid cell differentiation and enhances antitumor immunity in patients with lung cancer. Cancer Biother Radiopharm 2012; 27: 495–503.

    Article  CAS  Google Scholar 

  81. Huang HL, Chao MW, Chen CC, Cheng CC, Chen MC, Lin CF et al. LTP-1, a novel antimitotic agent and Stat3 inhibitor, inhibits human pancreatic carcinomas in vitro and in vivo. Sci Rep 2016; 6: 27794.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cell Biology, S. Arthur Localio Laboratory, New York University School of Medicine, New York, NY, USA

    M Pergamo & G Miller

Authors
  1. M Pergamo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Pergamo.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pergamo, M., Miller, G. Myeloid-derived suppressor cells and their role in pancreatic cancer. Cancer Gene Ther 24, 100–105 (2017). https://doi.org/10.1038/cgt.2016.65

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cgt.2016.65

This article is cited by

Search

Advanced search

Quick links