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Myeloid-derived suppressor cells are associated with disease progression and decreased overall survival in advanced-stage melanoma patients

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Abstract

Myeloid-derived suppressor cells are increased in the peripheral blood of advanced-stage cancer patients; however, no studies have shown a correlation of these immunosuppressive cells with clinical outcomes in melanoma patients. We characterized the frequency and suppressive function of multiple subsets of myeloid-derived suppressor cells in the peripheral blood of 34 patients with Stage IV melanoma, 20 patients with Stage I melanoma, and 15 healthy donors. The frequency of CD14+ MDSCs (Lin− CD11b+ HLA-DR− CD14+ CD33+) and CD14− MDSCs (Lin− CD11b+ HLA-DR− CD14− CD33+) was increased in the peripheral blood of Stage IV melanoma patients relative to healthy donors. The frequency of CD14+ and CD14− MDSCs correlated with each other and with the increased frequency of regulatory T cells, but not with classically defined monocytes. CD14− MDSCs isolated from the peripheral blood of Stage IV melanoma patients suppressed T cell activation more than those isolated from healthy donors, and the frequency of these cells correlated with disease progression and decreased overall survival. Our study provides the first evidence that the frequency of CD14− MDSCs negatively correlates with clinical outcomes in advanced-stage melanoma patients. These data indicate that suppressive MDSCs should be considered as targets for future immunotherapies.

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References

  1. Baumgartner JM, Gonzalez R, Lewis KD, Robinson WA, Richter DA, Palmer BE, Wilson CC, McCarter MD (2009) Increased survival from stage IV melanoma associated with fewer regulatory T Cells. J Surg Res 154:13–20

    Article  PubMed  CAS  Google Scholar 

  2. Cote AL, Usherwood EJ, Turk MJ (2008) Tumor-specific T-cell memory: clearing the regulatory T-cell hurdle. Cancer Res 68:1614–1617

    Article  PubMed  CAS  Google Scholar 

  3. Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M et al (1999) High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17:2105–2116

    PubMed  CAS  Google Scholar 

  4. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723

    Article  PubMed  CAS  Google Scholar 

  5. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454

    Article  PubMed  CAS  Google Scholar 

  6. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K et al (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366:2455–2465

    Article  PubMed  CAS  Google Scholar 

  7. Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, Citrin DE, Restifo NP, Robbins PF, Wunderlich JR et al (2011) Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res 17:4550–4557

    Article  PubMed  CAS  Google Scholar 

  8. Sarnaik AA, Yu B, Yu D, Morelli D, Hall M, Bogle D, Yan L, Targan S, Solomon J, Nichol G et al (2011) Extended dose ipilimumab with a peptide vaccine: immune correlates associated with clinical benefit in patients with resected high-risk stage IIIc/IV melanoma. Clin Cancer Res 17:896–906

    Article  PubMed  CAS  Google Scholar 

  9. Prieto PA, Yang JC, Sherry RM, Hughes MS, Kammula US, White DE, Levy CL, Rosenberg SA, Phan GQ (2012) CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma. Clin Cancer Res 18:2039–2047

    Article  PubMed  CAS  Google Scholar 

  10. Seung LP, Rowley DA, Dubey P, Schreiber H (1995) Synergy between T-cell immunity and inhibition of paracrine stimulation causes tumor rejection. Proc Natl Acad Sci USA 92:6254–6258

    Article  PubMed  CAS  Google Scholar 

  11. Pekarek LA, Starr BA, Toledano AY, Schreiber H (1995) Inhibition of tumor growth by elimination of granulocytes. J Exp Med 181:435–440

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  13. Movahedi K, Guilliams M, Van den Bossche J, Van den Bergh R, Gysemans C, Beschin A, De Baetselier P, Van Ginderachter JA (2008) Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood 111:4233–4244

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  16. Kusmartsev S, Nagaraj S, Gabrilovich DI (2005) Tumor-associated CD8+ T cell tolerance induced by bone marrow-derived immature myeloid cells. J Immunol 175:4583–4592

    PubMed  CAS  Google Scholar 

  17. 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  PubMed  CAS  Google Scholar 

  18. Almand B, Clark JI, Nikitina E, van Beynen J, English NR, Knight SC, Carbone DP, Gabrilovich DI (2001) Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol 166:678–689

    PubMed  CAS  Google Scholar 

  19. 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  PubMed  CAS  Google Scholar 

  20. Duffy A, Zhao F, Haile L, Gamrekelashvili J, Fioravanti S, Ma C, Kapanadze T, Compton K, Figg WD, Greten TF (2013) Comparative analysis of monocytic and granulocytic myeloid-derived suppressor cell subsets in patients with gastrointestinal malignancies. Cancer Immunol Immunother 62:299–307

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  23. Liu CY, Wang YM, Wang CL, Feng PH, Ko HW, Liu YH, Wu YC, Chu Y, Chung FT, Kuo CH 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  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  25. Rodrigues JC, Gonzalez GC, Zhang L, Ibrahim G, Kelly JJ, Gustafson MP, Lin Y, Dietz AB, Forsyth PA, Yong VW et al (2010) Normal human monocytes exposed to glioma cells acquire myeloid-derived suppressor cell-like properties. Neuro Oncol 12:351–365

    Article  PubMed  CAS  Google Scholar 

  26. Porembka MR, Mitchem JB, Belt BA, Hsieh CS, Lee HM, Herndon J, Gillanders WE, Linehan DC, Goedegebuure P (2012) Pancreatic adenocarcinoma induces bone marrow mobilization of myeloid-derived suppressor cells which promote primary tumor growth. Cancer Immunol Immunother 61:1373–1385

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  28. Mandruzzato S, Solito S, Falisi E, Francescato S, Chiarion-Sileni V, Mocellin S, Zanon A, Rossi CR, Nitti D, Bronte V et al (2009) IL4Ralpha+ myeloid-derived suppressor cell expansion in cancer patients. J Immunol 182:6562–6568

    Article  PubMed  CAS  Google Scholar 

  29. Mirza N, Fishman M, Fricke I, Dunn M, Neuger AM, Frost TJ, Lush RM, Antonia S, Gabrilovich DI (2006) All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients. Cancer Res 66:9299–9307

    Article  PubMed  CAS  Google Scholar 

  30. 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  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  32. 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  PubMed  CAS  Google Scholar 

  33. Solito S, Falisi E, Diaz-Montero CM, Doni A, Pinton L, Rosato A, Francescato S, Basso G, Zanovello P, Onicescu G 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  PubMed  CAS  Google Scholar 

  34. Mundy-Bosse BL, Young GS, Bauer T, Binkley E, Bloomston M, Bill MA, Bekaii-Saab T, Carson WE 3rd, Lesinski GB (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  PubMed  CAS  Google Scholar 

  35. Montero AJ, Diaz-Montero CM, Deutsch YE, Hurley J, Koniaris LG, Rumboldt T, Yasir S, Jorda M, Garret-Mayer E, Avisar E et al (2012) Phase 2 study of neoadjuvant treatment with NOV-002 in combination with doxorubicin and cyclophosphamide followed by docetaxel in patients with HER-2 negative clinical stage II-IIIc breast cancer. Breast Cancer Res Treat 132:215–223

    Article  PubMed  CAS  Google Scholar 

  36. Valenti R, Huber V, Filipazzi P, Pilla L, Sovena G, Villa A, Corbelli A, Fais S, Parmiani G, Rivoltini L (2006) Human tumor-released microvesicles promote the differentiation of myeloid cells with transforming growth factor-beta-mediated suppressive activity on T lymphocytes. Cancer Res 66:9290–9298

    Article  PubMed  CAS  Google Scholar 

  37. Filipazzi P, Valenti R, Huber V, Pilla L, Canese P, Iero M, Castelli C, Mariani L, Parmiani G, Rivoltini L (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  PubMed  CAS  Google Scholar 

  38. Tarhini AA, Butterfield LH, Shuai Y, Gooding WE, Kalinski P, Kirkwood JM (2012) Differing patterns of circulating regulatory T cells and myeloid-derived suppressor cells in metastatic melanoma patients receiving anti-CTLA4 antibody and interferon-alpha or TLR-9 agonist and GM-CSF with peptide vaccination. J Immunother 35:702–710

    Article  PubMed  CAS  Google Scholar 

  39. Ganguly D, Paul K, Bagchi J, Rakshit S, Mandal L, Bandyopadhyay G, Bandyopadhyay S (2007) Granulocyte-macrophage colony-stimulating factor drives monocytes to CD14low CD83+ DCSIGN- interleukin-10-producing myeloid cells with differential effects on T-cell subsets. Immunology 121:499–507

    Article  PubMed  CAS  Google Scholar 

  40. Tedder TF, Jansen PJ (2001) Isolation and generation of human dendritic cells. Curr Protoc Immunol Chapter 7: Unit 7 32

  41. 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  PubMed  CAS  Google Scholar 

  42. Gros A, Turcotte S, Wunderlich JR, Ahmadzadeh M, 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

    Article  PubMed  CAS  Google Scholar 

  43. Kodumudi KN, Weber A, Sarnaik AA, Pilon-Thomas S (2012) Blockade of myeloid-derived suppressor cells after induction of lymphopenia improves adoptive T cell therapy in a murine model of melanoma. J Immunol 189:5147–5154

    Google Scholar 

  44. Bunt SK, Yang L, Sinha P, Clements VK, Leips J, Ostrand-Rosenberg S (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  PubMed  CAS  Google Scholar 

  45. 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  PubMed  CAS  Google Scholar 

  46. Bronte V, Chappell DB, Apolloni E, Cabrelle A, Wang M, Hwu P, Restifo NP (1999) 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

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  48. Ostrand-Rosenberg S (2010) Myeloid-derived suppressor cells: more mechanisms for inhibiting antitumor immunity. Cancer Immunol Immunother 59:1593–1600

    Article  PubMed  Google Scholar 

  49. Corzo CA, Condamine T, Lu L, Cotter MJ, Youn JI, Cheng P, Cho HI, Celis E, Quiceno DG, Padhya T et al (2010) HIF-1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med 207:2439–2453

    Article  PubMed  CAS  Google Scholar 

  50. Yu J, Du W, Yan F, Wang Y, Li H, Cao S, Yu W, Shen C, Liu J, Ren X (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  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by a University of Colorado Cancer Center Fellowship, the University of Colorado Cancer Center Support Grant (P30CA046934), the American Cancer Society 2012 Roaring Fork Valley Postdoctoral Research Award, and the Conner Family Foundation Grant. We would like to thank the laboratory members of Dr. Virginia Borges and Dr. Pepper Schedin for critical reviews of the data and Eric Spongberg for his technical support. We would also like to thank Dr. Sonali Jindal and Pat Bell for their assistance and histology expertise.

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Surgery, School of Medicine, University of Colorado Denver Anschutz Medical Campus, Academic Office One, Mailstop C313, 12631 E. 17th Ave, Aurora, CO, 80045, USA

    Kimberly R. Jordan & Martin D. McCarter

  2. Division of Medical Oncology, School of Medicine, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA

    Rodabe N. Amaria, Oscar Ramirez, Eryn B. Callihan, Michelle Borakove, Elizabeth Manthey & Virginia F. Borges

  3. Department of Biostatistics and Informatics, School of Public Health, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA

    Dexiang Gao

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  1. Kimberly R. Jordan
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Correspondence to Martin D. McCarter.

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Jordan, K.R., Amaria, R.N., Ramirez, O. et al. Myeloid-derived suppressor cells are associated with disease progression and decreased overall survival in advanced-stage melanoma patients. Cancer Immunol Immunother 62, 1711–1722 (2013). https://doi.org/10.1007/s00262-013-1475-x

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