Skip to main content

Advertisement

SpringerLink
Log in

A clinical and biological perspective of human myeloid-derived suppressor cells in cancer

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Considering the large number of studies focused on myeloid-derived suppressor cells (MDSCs) to date, only a handful of well-defined relationships in human cancer have been established. The difficulty of assessing the impact of MDSCs in human cancer is partly due to the relatively small number of studies performed in humans. This is compounded in the literature by a common lack of clear indication of which species is being referred to for each characteristic described. These aspects may result in inappropriate extrapolation of animal studies to those in the human setting. This is especially the case for studies focused on investigating therapies which can be used to target MDSCs or those aimed at understanding their mechanism. Here, we attempt to rectify this by reviewing only studies on MDSC performed in humans. We survey studies which explore (1) whether MDSC levels are altered in cancer patients and if this is correlated with patient survival, (2) the so far identified mechanisms employed by MDSC to exert immune suppression, and (3) whether therapeutic agents can be used to target MDSCs by either altering their level, influencing their differentiation or inhibiting their suppressive function. Despite the fact that these studies clearly show that MDSCs are important in human cancer, the clinical employment of agents intended to target them has not yet been accomplished. We identify factors which have contributed to this and propose steps which may facilitate the translation of these therapies to the clinic in future.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. 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 

  2. Mantovani A (2010) The growing diversity and spectrum of action of myeloid-derived suppressor cells. Eur J Immunol 40:3317–3320

    Article  CAS  PubMed  Google Scholar 

  3. Gabrilovich DI, Bronte V, Chen SH, Colombo MP, Ochoa A, Ostrand-Rosenberg S et al (2007) The terminology issue for myeloid-derived suppressor cells. Cancer Res 67:425-426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yazdani Y, Mohammadnia-Afrouzi M, Yousefi M, Anvari E, Ghalamfarsa G, Hasannia H et al (2015) Myeloid-derived suppressor cells in B cell malignancies. Tumour Biol 36:7339–7353

    Article  CAS  PubMed  Google Scholar 

  6. Motallebnezhad M, Jadidi-Niaragh F, Qamsari ES, Bagheri S, Gharibi T, Yousefi M (2015) The immunobiology of myeloid-derived suppressor cells in cancer. Tumour Biol 37:1387–1406

  7. Poschke I, Kiessling R (2012) On the armament and appearances of human myeloid-derived suppressor cells. Clin Immunol 144:250–268

    Article  CAS  PubMed  Google Scholar 

  8. Filipazzi P, Valenti R, Huber V, Pilla L, Canese P, Iero M et al (2007) Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine. J Clin Oncol 25:2546–2553

    Article  CAS  PubMed  Google Scholar 

  9. Mandruzzato S, Solito S, Falisi E, Francescato S, Chiarion-Sileni V, Mocellin S et al (2009) IL4Ralpha+ myeloid-derived suppressor cell expansion in cancer patients. J Immunol 182:6562–6568

    Article  CAS  PubMed  Google Scholar 

  10. Schmielau J, Finn OJ (2001) Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of T-cell function in advanced cancer patients. Cancer Res 61:4756–4760

    CAS  PubMed  Google Scholar 

  11. Zea AH, Rodriguez PC, Atkins MB, Hernandez C, Signoretti S, Zabaleta J et al (2005) Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res 65:3044–3048

    CAS  PubMed  Google Scholar 

  12. Rodriguez PC, Ernstoff MS, Hernandez C, Atkins M, Zabaleta J, Sierra R et al (2009) Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes. Cancer Res 69:1553–1560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Solito S, Falisi E, Diaz-Montero CM, Doni A, Pinton L, Rosato A et al (2011) A human promyelocytic-like population is responsible for the immune suppression mediated by myeloid-derived suppressor cells. Blood 118:2254–2265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ (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 

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

    Article  CAS  PubMed  Google Scholar 

  16. Mao Y, Sarhan D, Steven A, Seliger B, Kiessling R, Lundqvist A (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 

  17. Mao Y, Poschke I, Wennerberg E, Pico de Coana Y, Egyhazi Brage S, Schultz I 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 

  18. Yu J, Wang Y, Yan F, Zhang P, Li H, Zhao H et al (2014) Noncanonical NF-kappaB activation mediates STAT3-stimulated IDO upregulation in myeloid-derived suppressor cells in breast cancer. J Immunol 193:2574–2586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Parmiani G, Castelli C, Pilla L, Santinami M, Colombo MP, Rivoltini L (2007) Opposite immune functions of GM-CSF administered as vaccine adjuvant in cancer patients. Ann Oncol 18:226–232

    Article  CAS  PubMed  Google Scholar 

  20. Marigo I, Bosio E, Solito S, Mesa C, Fernandez A, Dolcetti L et al (2010) Tumor-induced tolerance and immune suppression depend on the C/EBPbeta transcription factor. Immunity 32:790–802

    Article  CAS  PubMed  Google Scholar 

  21. 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  PubMed Central  Google Scholar 

  22. Mundy-Bosse BL, Young GS, Bauer T, Binkley E, Bloomston M, Bill MA et al (2011) Distinct myeloid suppressor cell subsets correlate with plasma IL-6 and IL-10 and reduced interferon-alpha signaling in CD4(+) T cells from patients with GI malignancy. Cancer Immunol Immunother 60:1269–1279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gabitass RF, Annels NE, Stocken DD, Pandha HA, Middleton GW (2011) Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13. Cancer Immunol Immunother 60:1419–1430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lechner MG, Megiel C, Russell SM, Bingham B, Arger N, Woo T et al (2011) Functional characterization of human Cd33+ and Cd11b+ myeloid-derived suppressor cell subsets induced from peripheral blood mononuclear cells co-cultured with a diverse set of human tumor cell lines. J Transl Med. 9:90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD et al (2006) Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 355:1018–1028

    Article  CAS  PubMed  Google Scholar 

  26. Wesolowski R, Markowitz J, Carson WE 3rd (2013) Myeloid derived suppressor cells—a new therapeutic target in the treatment of cancer. J Immunother Cancer. 1:10

    Article  PubMed  PubMed Central  Google Scholar 

  27. Rudolph BM, Loquai C, Gerwe A, Bacher N, Steinbrink K, Grabbe S et al (2014) Increased frequencies of CD11b(+) CD33(+) CD14(+) HLA-DR(low) myeloid-derived suppressor cells are an early event in melanoma patients. Exp Dermatol 23:202–204

    Article  CAS  PubMed  Google Scholar 

  28. Jordan KR, Amaria RN, Ramirez O, Callihan EB, Gao D, Borakove M 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 

  29. Jiang H, Gebhardt C, Umansky L, Beckhove P, Schulze TJ, Utikal J et al (2015) Elevated chronic inflammatory factors and myeloid-derived suppressor cells indicate poor prognosis in advanced melanoma patients. Int J Cancer 136:2352–2360

    Article  CAS  PubMed  Google Scholar 

  30. Gros A, Turcotte S, Ahmadzadeh M, Wunderlich JR, Dudley ME, Rosenberg SA (2012) Myeloid cells obtained from the blood but not from the tumor can suppress T cell proliferation in patients with melanoma. Clin Cancer Res 18:5212–5223

    CAS  Google Scholar 

  31. Kitano S, Postow MA, Ziegler CG, Kuk D, Panageas KS, Cortez C et al (2014) Computational algorithm-driven evaluation of monocytic myeloid-derived suppressor cell frequency for prediction of clinical outcomes. Cancer Immunol Res 2:812–821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Schilling B, Sucker A, Griewank K, Zhao F, Weide B, Gorgens A et al (2013) Vemurafenib reverses immunosuppression by myeloid derived suppressor cells. Int J Cancer 133:1653–1663

    Article  CAS  PubMed  Google Scholar 

  33. Poschke I, Mougiakakos D, Hansson J, Masucci GV, Kiessling R (2010) Immature immunosuppressive CD14+ HLA-DR−/low cells in melanoma patients are Stat3hi and overexpress CD80, CD83, and DC-sign. Cancer Res 70:4335–4345

    Article  CAS  PubMed  Google Scholar 

  34. Meyer C, Cagnon L, Costa-Nunes CM, Baumgaertner P, Montandon N, Leyvraz L, et al (2013) Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab. Cancer Immunol Immunother 63:247–257

    Article  PubMed  CAS  Google Scholar 

  35. Vuk-Pavlovic S, Bulur PA, Lin Y, Qin R, Szumlanski CL, Zhao X et al (2010) Immunosuppressive CD14+HLA-DRlow/− monocytes in prostate cancer. Prostate 70:443–455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Idorn M, Kollgaard T, Kongsted P, Sengelov L, Thor Straten P (2014) Correlation between frequencies of blood monocytic myeloid-derived suppressor cells, regulatory T cells and negative prognostic markers in patients with castration-resistant metastatic prostate cancer. Cancer Immunol Immunother 63:1177–1187

    Article  CAS  PubMed  Google Scholar 

  37. Yuan XK, Zhao XK, Xia YC, Zhu X, Xiao P (2011) Increased circulating immunosuppressive CD14(+)HLA-DR(-/low) cells correlate with clinical cancer stage and pathological grade in patients with bladder carcinoma. J Int Med Res 39:1381–1391

    Article  CAS  PubMed  Google Scholar 

  38. Arihara F, Mizukoshi E, Kitahara M, Takata Y, Arai K, Yamashita T et al (2013) 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

    Article  CAS  PubMed  Google Scholar 

  39. Hoechst B, Ormandy LA, Ballmaier M, Lehner F, Kruger C, Manns MP et al (2008) A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology 135:234–243

    Article  CAS  PubMed  Google Scholar 

  40. Huang A, Zhang B, Wang B, Zhang F, Fan KX, Guo YJ (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 

  41. Vetsika EK, Koinis F, Gioulbasani M, Aggouraki D, Koutoulaki A, Skalidaki E et al (2014) A circulating subpopulation of monocytic myeloid-derived suppressor cells as an independent prognostic/predictive factor in untreated non-small lung cancer patients. J Immunol Res. 2014:659294

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Liu J, Zhou Y, Huang Q, Qiu L (2015) CD14HLA-DR expression: a novel prognostic factor in chronic lymphocytic leukemia. Oncol Lett. 9:1167–1172

    PubMed  Google Scholar 

  43. Chen MF, Kuan FC, Yen TC, Lu MS, Lin PY, Chung YH et al (2014) 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

    Article  PubMed  PubMed Central  Google Scholar 

  44. Huang H, Zhang G, Li G, Ma H, Zhang X (2015) Circulating CD14HLA-DR myeloid-derived suppressor cell is an indicator of poor prognosis in patients with ESCC. Tumour Biol 36:7987–7996

    Article  CAS  PubMed  Google Scholar 

  45. Romano A, Parrinello NL, Vetro C, Forte S, Chiarenza A, Figuera A et al (2015) 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

    Article  CAS  PubMed  Google Scholar 

  46. Walter S, Weinschenk T, Stenzl A, Zdrojowy R, Pluzanska A, Szczylik C, et al (2012) Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat Med 18:1254–1261

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Huang H, Zhang G, Li G, Ma H, Zhang X (2015) Circulating CD14(+)HLA-DR(-/low) myeloid-derived suppressor cell is an indicator of poor prognosis in patients with ESCC. Tumour Biol 36:7987–7996

    Article  CAS  PubMed  Google Scholar 

  49. Liu CY, Wang YM, Wang CL, Feng PH, Ko HW, Liu YH et al (2010) Population alterations of L-arginase- and inducible nitric oxide synthase-expressed CD11b+/CD14(-)/CD15+/CD33+ myeloid-derived suppressor cells and CD8+ T lymphocytes in patients with advanced-stage non-small cell lung cancer. J Cancer Res Clin Oncol 136:35–45

    Article  CAS  PubMed  Google Scholar 

  50. Chen HM, Ma G, Gildener-Leapman N, Eisenstein S, Coakley BA, Ozao J et al (2015) Myeloid-derived suppressor cells as an immune parameter in patients with concurrent sunitinib and stereotactic body radiotherapy. Clin Cancer Res 21:4073–4085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Trellakis S, Bruderek K, Hutte J, Elian M, Hoffmann TK, Lang S et al (2013) Granulocytic myeloid-derived suppressor cells are cryosensitive and their frequency does not correlate with serum concentrations of colony-stimulating factors in head and neck cancer. Innate Immun. 19:328–336

    Article  PubMed  CAS  Google Scholar 

  52. Eruslanov E, Neuberger M, Daurkin I, Perrin GQ, Algood C, Dahm P et al (2012) Circulating and tumor-infiltrating myeloid cell subsets in patients with bladder cancer. Int J Cancer 130:1109–1119

    Article  CAS  PubMed  Google Scholar 

  53. Hossain DM, Pal SK, Moreira D, Duttagupta P, Zhang Q, Won H 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 

  54. Khaled YS, Ammori BJ, Elkord E (2014) Increased levels of granulocytic myeloid-derived suppressor cells in peripheral blood and tumour tissue of pancreatic cancer patients. J Immunol Res 2014:879897

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Wang L, Chang EW, Wong SC, Ong SM, Chong DQ, Ling KL (2013) Increased myeloid-derived suppressor cells in gastric cancer correlate with cancer stage and plasma S100A8/A9 proinflammatory proteins. J Immunol 190:794–804

    Article  CAS  PubMed  Google Scholar 

  56. Choi J, Suh B, Ahn YO, Kim TM, Lee JO, Lee SH et al (2012) CD15+/CD16low human granulocytes from terminal cancer patients: granulocytic myeloid-derived suppressor cells that have suppressive function. Tumour Biol 33:121–129

    Article  CAS  PubMed  Google Scholar 

  57. Wu WC, Sun HW, Chen HT, Liang J, Yu XJ, Wu C et al (2014) Circulating hematopoietic stem and progenitor cells are myeloid-biased in cancer patients. Proc Natl Acad Sci USA 111:4221–4226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Chi N, Tan Z, Ma K, Bao L, Yun Z (2014) Increased circulating myeloid-derived suppressor cells correlate with cancer stages, interleukin-8 and -6 in prostate cancer. Int J Clin Exp Med 7:3181–3192

    PubMed  PubMed Central  Google Scholar 

  59. Chevolet I, Speeckaert R, Schreuer M, Neyns B, Krysko O, Bachert C et al (2015) Clinical significance of plasmacytoid dendritic cells and myeloid-derived suppressor cells in melanoma. J Transl Med 13:9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Yu J, Du W, Yan F, Wang Y, Li H, Cao S 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Sun HL, Zhou X, Xue YF, Wang K, Shen YF, Mao JJ et al (2012) Increased frequency and clinical significance of myeloid-derived suppressor cells in human colorectal carcinoma. World J Gastroenterol 18:3303–3309

    PubMed  PubMed Central  Google Scholar 

  63. Markowitz J, Brooks TR, Duggan MC, Paul BK, Pan X, Wei L et al (2015) Patients with pancreatic adenocarcinoma exhibit elevated levels of myeloid-derived suppressor cells upon progression of disease. Cancer Immunol Immunother 64:149–159

    Article  CAS  PubMed  Google Scholar 

  64. Mabuchi S, Matsumoto Y, Kawano M, Minami K, Seo Y, Sasano T, et al (2014) Uterine cervical cancer displaying tumor-related leukocytosis: a distinct clinical entity with radioresistant feature. J Natl Cancer Inst 106(7):dju147. doi:10.1093/jnci/dju147

  65. Wang D, An G, Xie S, Yao Y, Feng G (2016) The clinical and prognostic significance of CD14HLA-DR myeloid-derived suppressor cells in hepatocellular carcinoma patients receiving radiotherapy. Tumour Biol. (Epub ahead of print)

  66. Meyer C, Cagnon L, Costa-Nunes CM, Baumgaertner P, Montandon N, Leyvraz L 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 

  67. Poschke I, Mao Y, Adamson L, Salazar-Onfray F, Masucci G, Kiessling R (2012) Myeloid-derived suppressor cells impair the quality of dendritic cell vaccines. Cancer Immunol Immunother 61:827–838

    Article  CAS  PubMed  Google Scholar 

  68. Cui TX, Kryczek I, Zhao L, Zhao E, Kuick R, Roh MH et al (2013) Myeloid-derived suppressor cells enhance stemness of cancer cells by inducing microRNA101 and suppressing the corepressor CtBP2. Immunity 39:611–621

    Article  CAS  PubMed  Google Scholar 

  69. Weide B, Martens A, Zelba H, Stutz C, Derhovanessian E, Di Giacomo AM 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 

  70. Weide B, Zelba H, Derhovanessian E, Pflugfelder A, Eigentler TK, Di Giacomo AM et al (2012) Functional T cells targeting NY-ESO-1 or Melan-A are predictive for survival of patients with distant melanoma metastasis. J Clin Oncol 30:1835–1841

    Article  CAS  PubMed  Google Scholar 

  71. Bailur JK, Gueckel B, Derhovanessian E, Pawelec G (2015) Presence of circulating Her2-reactive CD8+ T-cells is associated with lower frequencies of myeloid-derived suppressor cells and regulatory T cells, and better survival in older breast cancer patients. Breast Cancer Res 17:34

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Walter S, Weinschenk T, Stenzl A, Zdrojowy R, Pluzanska A, Szczylik C et al (2012) Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat Med 18:1254–1261

    Article  CAS  PubMed  Google Scholar 

  73. Filipazzi P, Pilla L, Mariani L, Patuzzo R, Castelli C, Camisaschi C, et al (2012) Limited Induction of Tumor-cross-reactive T cells without a measurable clinical benefit in early melanoma patients vaccinated with human leukocyte antigen-class I-modified peptides. Clin Cancer Res 18:6485–6496

    Article  CAS  PubMed  Google Scholar 

  74. Martens A, Wistuba-Hamprecht K, Geukes Foppen MH, Yuan J, Postow MA, Wong P, et al (2016) Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab. Clin Cancer Res. (Epub ahead of print)

  75. Santegoets SJ, Stam AG, Lougheed SM, Gall H, Jooss K, Sacks N 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 

  76. Hansen GL, Gaudernack G, Brunsvig PF, Cvancarova M, Kyte JA (2015) Immunological factors influencing clinical outcome in lung cancer patients after telomerase peptide vaccination. Cancer Immunol Immunother 64:1609–1621

    Article  CAS  PubMed  Google Scholar 

  77. Tarhini AA, Edington H, Butterfield LH, Lin Y, Shuai Y, Tawbi H et al (2014) Immune monitoring of the circulation and the tumor microenvironment in patients with regionally advanced melanoma receiving neoadjuvant ipilimumab. PLoS One 9:e87705

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Mandruzzato S, Brandau S, Britten CM, Bronte V, Damuzzo V, Gouttefangeas C, et al (2016) Toward harmonized phenotyping of human myeloid-derived suppressor cells by flow cytometry: results from an interim study. Cancer Immunol Immunother 65:161–169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Kotsakis A, Harasymczuk M, Schilling B, Georgoulias V, Argiris A, Whiteside TL (2012) Myeloid-derived suppressor cell measurements in fresh and cryopreserved blood samples. J Immunol Methods 381:14–22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Mao Y, Poschke I, Wennerberg E, Pico de Coana Y, Brage SE, Schultz I, 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 

  81. Schmidt H, Bastholt L, Geertsen P, Christensen IJ, Larsen S, Gehl J et al (2005) Elevated neutrophil and monocyte counts in peripheral blood are associated with poor survival in patients with metastatic melanoma: a prognostic model. Br J Cancer 93:273–278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Vignali DA, Collison LW, Workman CJ (2008) How regulatory T cells work. Nat Rev Immunol 8:523–532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Rodriguez PC, Quiceno DG, Ochoa AC (2007) l-arginine availability regulates T-lymphocyte cell-cycle progression. Blood 109:1568–1573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Schieber M, Chandel NS (2014) ROS function in redox signaling and oxidative stress. Curr Biol 24:R453–R462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Yoshimura A, Muto G (2011) TGF-beta function in immune suppression. Curr Top Microbiol Immunol 350:127–147

    CAS  PubMed  Google Scholar 

  86. Kalinski P (2012) Regulation of immune responses by prostaglandin E2. J Immunol 188:21–28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kortylewski M, Yu H (2008) Role of Stat3 in suppressing anti-tumor immunity. Curr Opin Immunol 20:228–233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Jitschin R, Braun M, Buttner M, Dettmer-Wilde K, Bricks J, Berger J et al (2014) CLL-cells induce IDOhi CD14+HLA-DRlo myeloid-derived suppressor cells that inhibit T-cell responses and promote TRegs. Blood 124:750–760

    Article  CAS  PubMed  Google Scholar 

  89. Mao Y, Sarhan D, Steven A, Seliger B, Kiessling R, Lundqvist A (2014) Inhibition of tumor-derived prostaglandin-E2 blocks the induction of myeloid-derived suppressor cells and recovers natural killer cell activity. Clin Cancer Res

  90. Gorgun GT, Whitehill G, Anderson JL, Hideshima T, Maguire C, Laubach J et al (2013) Tumor-promoting immune-suppressive myeloid-derived suppressor cells in the multiple myeloma microenvironment in humans. Blood 121:2975–2987

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Chikamatsu K, Sakakura K, Toyoda M, Takahashi K, Yamamoto T, Masuyama K (2012) Immunosuppressive activity of CD14+HLA-DR−cells in squamous cell carcinoma of the head and neck. Cancer Sci 103:976–983

    Article  CAS  PubMed  Google Scholar 

  92. Mirza N, Fishman M, Fricke I, Dunn M, Neuger AM, Frost TJ et al (2006) All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients. Cancer Res 66:9299–9307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Busch A, Zeh D, Janzen V, Mugge LO, Wolf D, Fingerhut L et al (2014) Treatment with lenalidomide induces immunoactivating and counter-regulatory immunosuppressive changes in myeloma patients. Clin Exp Immunol 177:439–453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. van Cruijsen H, van der Veldt AA, Vroling L, Oosterhoff D, Broxterman HJ, Scheper RJ et al (2008) Sunitinib-induced myeloid lineage redistribution in renal cell cancer patients: CD1c+ dendritic cell frequency predicts progression-free survival. Clin Cancer Res 14:5884–5892

    Article  PubMed  CAS  Google Scholar 

  95. Annels NE, Shaw VE, Gabitass RF, Billingham L, Corrie P, Eatock M et al (2014) The effects of gemcitabine and capecitabine combination chemotherapy and of low-dose adjuvant GM-CSF on the levels of myeloid-derived suppressor cells in patients with advanced pancreatic cancer. Cancer Immunol Immunother 63:175–183

    Article  CAS  PubMed  Google Scholar 

  96. Wang Z, Zhang L, Wang H, Xiong S, Li Y, Tao Q et al (2015) 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

    Article  CAS  PubMed  Google Scholar 

  97. Ko JS, Zea AH, Rini BI, Ireland JL, Elson P, Cohen P et al (2009) Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res 15:2148–2157

    Article  CAS  PubMed  Google Scholar 

  98. Guislain A, Gadiot J, Kaiser A, Jordanova ES, Broeks A, Sanders J 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 

  99. Pico de Coana Y, Poschke I, Gentilcore G, Mao Y, Nystrom M, Hansson J et al (2013) Ipilimumab treatment results in an early decrease in the frequency of circulating granulocytic myeloid-derived suppressor cells as well as their Arginase1 production. Cancer Immunol Res. 1:158–162

    Article  CAS  PubMed  Google Scholar 

  100. Gebhardt C, Sevko A, Jiang H, Lichtenberger R, Reith M, Tarnanidis K, et al (2015) Myeloid Cells and Related Chronic Inflammatory Factors as Novel Predictive Markers in Melanoma Treatment with Ipilimumab. Clin Cancer Res

  101. Weide B, Eigentler TK, Pflugfelder A, Zelba H, Martens A, Pawelec G et al (2014) Intralesional treatment of stage III metastatic melanoma patients with L19-IL2 results in sustained clinical and systemic immunologic responses. Cancer Immunol Res. 2:668–678

    Article  CAS  PubMed  Google Scholar 

  102. Weed DT, Vella JL, Reis IM, De la Fuente AC, Gomez C, Sargi Z 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 

  103. Califano JA, Khan Z, Noonan KA, Rudraraju L, Zhang Z, Wang H 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 

  104. Iclozan C, Antonia S, Chiappori A, Chen DT, Gabrilovich D (2013) Therapeutic regulation of myeloid-derived suppressor cells and immune response to cancer vaccine in patients with extensive stage small cell lung cancer. Cancer Immunol Immunother 62:909–918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Nagaraj S, Youn JI, Weber H, Iclozan C, Lu L, Cotter MJ et al (2010) Anti-inflammatory triterpenoid blocks immune suppressive function of MDSCs and improves immune response in cancer. Clin Cancer Res 16:1812–1823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Fricke I, Mirza N, Dupont J, Lockhart C, Jackson A, Lee JH et al (2007) Vascular endothelial growth factor-trap overcomes defects in dendritic cell differentiation but does not improve antigen-specific immune responses. Clin Cancer Res 13:4840–4848

    Article  CAS  PubMed  Google Scholar 

  107. Sanford DE, Porembka MR, Panni RZ, Mitchem JB, Belt BA, Plambeck-Suess SM et al (2013) A study of Zoledronic acid as neo-adjuvant, perioperative therapy in patients with resectable pancreatic ductal adenocarcinoma. J Cancer Ther. 4:797–803

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Heine A, Schilling J, Grunwald B, Kruger A, Gevensleben H, Held SA, et al (2016) The induction of human myeloid derived suppressor cells through hepatic stellate cells is dose-dependently inhibited by the tyrosine kinase inhibitors nilotinib, dasatinib and sorafenib, but not sunitinib. Cancer Immunol Immunother

  109. Serafini P, Meckel K, Kelso M, Noonan K, Califano J, Koch W 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 

  110. Kusmartsev S, Su Z, Heiser A, Dannull J, Eruslanov E, Kubler H et al (2008) Reversal of myeloid cell-mediated immunosuppression in patients with metastatic renal cell carcinoma. Clin Cancer Res 14:8270–8278

    Article  CAS  PubMed  Google Scholar 

  111. Chalmin F, Ladoire S, Mignot G, Vincent J, Bruchard M, Remy-Martin JP et al (2010) Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J Clin Invest 120:457–471

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Song F, Parekh S, Hooper L, Loke YK, Ryder J, Sutton AJ, et al. Dissemination and publication of research findings: an updated review of related biases. Health Technol Assess. 2010;14:iii, ix–xi, 1–193

  113. McGauran N, Wieseler B, Kreis J, Schuler YB, Kolsch H, Kaiser T (2010) Reporting bias in medical research—a narrative review. Trials 11:37

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Easterbrook PJ, Berlin JA, Gopalan R, Matthews DR (1991) Publication bias in clinical research. Lancet 337:867–872

    Article  CAS  PubMed  Google Scholar 

  115. Gebhardt C, Sevko A, Jiang H, Lichtenberger R, Reith M, Tarnanidis K 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 

  116. Gorgun G, Samur MK, Cowens KB, Paula S, Bianchi G, Anderson JE et al (2015) Lenalidomide enhances immune checkpoint blockade-induced immune response in multiple myeloma. Clin Cancer Res 21:4607–4618

    Article  PubMed  CAS  Google Scholar 

  117. 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 

  118. Hoechst B, Voigtlaender T, Ormandy L, Gamrekelashvili J, Zhao F, Wedemeyer H et al (2009) Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology 50:799–807

    Article  CAS  PubMed  Google Scholar 

  119. Poschke I, Mao Y, Adamson L, Salazar-Onfray F, Masucci G, Kiessling R (2011) Myeloid-derived suppressor cells impair the quality of dendritic cell vaccines. Cancer Immunol Immunother 61:827–838

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by Grants from the German Research Foundation (GP) (DFG Pa 361/22-1) and the fortüne program of the University Hospital Tübingen (CS) (F 1282980).

Author information

Authors and Affiliations

  1. Second Department of Internal Medicine, University Hospital Tübingen, Waldhörnlestr. 22, 72072, Tübingen, Germany

    Christopher Shipp, Lisa Speigl, Nicole Janssen, Alexander Martens & Graham Pawelec

  2. Department of Dermatology, University Hospital Tübingen, Liebermeisterstr. 24, 72076, Tübingen, Germany

    Alexander Martens

  3. School of Science and Technology, College of Arts and Science, Nottingham Trent University, Burton St, Nottingham, NG1 4BU, UK

    Graham Pawelec

Authors
  1. Christopher Shipp
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lisa Speigl
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nicole Janssen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alexander Martens
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Graham Pawelec
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Christopher Shipp or Graham Pawelec.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shipp, C., Speigl, L., Janssen, N. et al. A clinical and biological perspective of human myeloid-derived suppressor cells in cancer. Cell. Mol. Life Sci. 73, 4043–4061 (2016). https://doi.org/10.1007/s00018-016-2278-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-016-2278-y

Keywords

Search

Navigation