Cancer Immunology, Immunotherapy

, Volume 63, Issue 3, pp 247–257 | Cite as

Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab

  • Christiane Meyer
  • Laurène Cagnon
  • Carla M. Costa-Nunes
  • Petra Baumgaertner
  • Nicole Montandon
  • Loredana Leyvraz
  • Olivier Michielin
  • Emanuela Romano
  • Daniel E. Speiser
Original Article


Metastatic melanoma has a poor prognosis with high resistance to chemotherapy and radiation. Recently, the anti-CTLA-4 antibody ipilimumab has demonstrated clinical efficacy, being the first agent to significantly prolong the overall survival of inoperable stage III/IV melanoma patients. A major aim of patient immune monitoring is the identification of biomarkers that predict clinical outcome. We studied circulating myeloid-derived suppressor cells (MDSC) in ipilimumab-treated patients to detect alterations in the myeloid cell compartment and possible correlations with clinical outcome. Lin CD14+ HLA-DR monocytic MDSC were enriched in peripheral blood of melanoma patients compared to healthy donors (HD). Tumor resection did not significantly alter MDSC frequencies. During ipilimumab treatment, MDSC frequencies did not change significantly compared to baseline levels. We observed high inter-patient differences. MDSC frequencies in ipilimumab-treated patients were independent of baseline serum lactate dehydrogenase levels but tended to increase in patients with severe metastatic disease (M1c) compared to patients with metastases in skin or lymph nodes only (M1a), who had frequencies comparable to HD. Interestingly, clinical responders to ipilimumab therapy showed significantly less lin CD14+ HLA-DR cells as compared to non-responders. The data suggest that the frequency of monocytic MDSC may be used as predictive marker of response, as low frequencies identify patients more likely benefitting from ipilimumab treatment. Prospective clinical trials assessing MDSC frequencies as potential biomarkers are warranted to validate these observations.


MDSC Ipilimumab CTLA-4 Melanoma 

Supplementary material

262_2013_1508_MOESM1_ESM.pdf (810 kb)
Supplementary material 1 (PDF 810 kb)


  1. 1.
    Garbe C, Eigentler TK, Keilholz U, Hauschild A, Kirkwood JM (2011) Systematic review of medical treatment in melanoma: current status and future prospects. Oncologist 16(1):5–24PubMedCrossRefGoogle Scholar
  2. 2.
    Rosenberg SA, Dudley ME (2009) Adoptive cell therapy for the treatment of patients with metastatic melanoma. Curr Opin Immunol 21(2):233–240PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C, Kunkel L, Rosenberg SA (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(7):2105–2116PubMedGoogle Scholar
  4. 4.
    Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, McArthur GA, Hutson TE, Moschos SJ, Flaherty KT, Hersey P, Kefford R, Lawrence D, Puzanov I, Lewis KD, Amaravadi RK, Chmielowski B, Lawrence HJ, Shyr Y, Ye F, Li J, Nolop KB, Lee RJ, Joe AK, Ribas A (2012) Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 366(8):707–714PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P, Dummer R, Trefzer U, Larkin JM, Utikal J, Dreno B, Nyakas M, Middleton MR, Becker JC, Casey M, Sherman LJ, Wu FS, Ouellet D, Martin AM, Patel K, Schadendorf D (2012) Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 367(2):107–114PubMedCrossRefGoogle Scholar
  6. 6.
    Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O’Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364(26):2507–2516PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, Kudchadkar R, Burris HA 3rd, Falchook G, Algazi A, Lewis K, Long GV, Puzanov I, Lebowitz P, Singh A, Little S, Sun P, Allred A, Ouellet D, Kim KB, Patel K, Weber J (2012) Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 367(18):1694–1703PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Robert C, Thomas L, Bondarenko I, O’Day S, M D J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Jr Miller WH, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364(26):2517–2526PubMedCrossRefGoogle Scholar
  10. 10.
    Sondak VK, Smalley KS, Kudchadkar R, Grippon S, Kirkpatrick P (2011) Ipilimumab. Nat Rev Drug Discov 10(6):411–412PubMedCrossRefGoogle Scholar
  11. 11.
    Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264PubMedCrossRefGoogle Scholar
  12. 12.
    Baitsch L, Baumgaertner P, Devevre E, Raghav SK, Legat A, Barba L, Wieckowski S, Bouzourene H, Deplancke B, Romero P, Rufer N, Speiser DE (2011) Exhaustion of tumor-specific CD8+ T cells in metastases from melanoma patients. J Clin Invest 121(6):2350–2360PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Weber JS, Hamid O, Chasalow SD, Wu DY, Parker SM, Galbraith S, Gnjatic S, Berman D (2011) Ipilimumab increases activated T cells and enhances humoral immunity in patients with advanced melanoma. J Immunother 35(1):89–97CrossRefGoogle Scholar
  14. 14.
    Wang W, Yu D, Sarnaik AA, Yu B, Hall M, Morelli D, Zhang Y, Zhao X, Weber JS (2012) Biomarkers on melanoma patient T cells associated with ipilimumab treatment. J Transl Med 10(1):146–158PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Attia P, Phan GQ, Maker AV, Robinson MR, Quezado MM, Yang JC, Sherry RM, Topalian SL, Kammula US, Royal RE, Restifo NP, Haworth LR, Levy C, Mavroukakis SA, Nichol G, Yellin MJ, Rosenberg SA (2005) Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol 23(25):6043–6053PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Hwu P (2010) Treating cancer by targeting the immune system. N Engl J Med 363(8):779–781PubMedCrossRefGoogle Scholar
  17. 17.
    Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbe C, Maio M, Binder M, Bohnsack O, Nichol G, Humphrey R, Hodi FS (2009) Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 15(23):7412–7420PubMedCrossRefGoogle Scholar
  18. 18.
    Ku GY, Yuan J, Page DB, Schroeder SE, Panageas KS, Carvajal RD, Chapman PB, Schwartz GK, Allison JP, Wolchok JD (2010) Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates with survival. Cancer 116(7):1767–1775PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Carthon BC, Wolchok JD, Yuan J, Kamat A, Ng Tang DS, Sun J, Ku G, Troncoso P, Logothetis CJ, Allison JP, Sharma P (2010) Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial. Clin Cancer Res 16(10):2861–2871PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Di Giacomo AM, Calabro L, Danielli R, Fonsatti E, Bertocci E, Pesce I, Fazio C, Cutaia O, Giannarelli D, Miracco C, Biagioli M, Altomonte M, Maio M (2013) Long-term survival and immunological parameters in metastatic melanoma patients who responded to ipilimumab 10 mg/kg within an expanded access programme. Cancer Immunol Immunother 62(6):1021–1028PubMedCrossRefGoogle Scholar
  21. 21.
    Yuan J, Adamow M, Ginsberg BA, Rasalan TS, Ritter E, Gallardo HF, Xu Y, Pogoriler E, Terzulli SL, Kuk D, Panageas KS, Ritter G, Sznol M, Halaban R, Jungbluth AA, Allison JP, Old LJ, Wolchok JD, Gnjatic S (2011) Integrated NY-ESO-1 antibody and CD8 + T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab. Proc Natl Acad Sci USA 108(40):16723–16728PubMedCrossRefGoogle Scholar
  22. 22.
    Yuan J, Ginsberg B, Page D, Li Y, Rasalan T, Gallardo HF, Xu Y, Adams S, Bhardwaj N, Busam K, Old LJ, Allison JP, Jungbluth A, Wolchok JD (2011) CTLA-4 blockade increases antigen-specific CD8(+) T cells in prevaccinated patients with melanoma: three cases. Cancer Immunol Immunother 60(8):1137–1146PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Liakou CI, Kamat A, Tang DN, Chen H, Sun J, Troncoso P, Logothetis C, Sharma P (2008) CTLA-4 blockade increases IFNgamma-producing CD4 + ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients. Proc Natl Acad Sci USA 105(39):14987–14992PubMedCrossRefGoogle Scholar
  24. 24.
    Pedicord VA, Montalvo W, Leiner IM, Allison JP (2010) Single dose of anti-CTLA-4 enhances CD8 + T-cell memory formation, function, and maintenance. Proc Natl Acad Sci USA 108(1):266–271PubMedCrossRefGoogle Scholar
  25. 25.
    Greten TF, Manns MP, Korangy F (2011) Myeloid derived suppressor cells in human diseases. Int Immunopharmacol 11(7):802–807PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Filipazzi P, Huber V, Rivoltini L (2011) Phenotype, function and clinical implications of myeloid-derived suppressor cells in cancer patients. Cancer Immunol Immunother 61(2):255–263PubMedCrossRefGoogle Scholar
  27. 27.
    Nagaraj S, Gabrilovich DI (2010) Myeloid-derived suppressor cells in human cancer. Cancer J 16(4):348–353PubMedCrossRefGoogle Scholar
  28. 28.
    Dumitru CA, Moses K, Trellakis S, Lang S, Brandau S (2012) Neutrophils and granulocytic myeloid-derived suppressor cells: immunophenotyping, cell biology and clinical relevance in human oncology. Cancer Immunol Immunother 61(8):1155–1167PubMedCrossRefGoogle Scholar
  29. 29.
    Gabrilovich DI, Ostrand-Rosenberg S, Bronte V (2012) Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 12(4):253–268PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    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(11):4335–4345PubMedCrossRefGoogle Scholar
  31. 31.
    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(18):2546–2553PubMedCrossRefGoogle Scholar
  32. 32.
    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(19):5212–5223PubMedCrossRefGoogle Scholar
  33. 33.
    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(24):8270–8278PubMedCrossRefGoogle Scholar
  34. 34.
    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(18):9299–9307PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    van Cruijsen H, van der Veldt AA, Vroling L, Oosterhoff D, Broxterman HJ, Scheper RJ, Giaccone G, Haanen JB, van den Eertwegh AJ, Boven E, Hoekman K, de Gruijl TD (2008) Sunitinib-induced myeloid lineage redistribution in renal cell cancer patients: CD1c + dendritic cell frequency predicts progression-free survival. Clin Cancer Res 14(18):5884–5892PubMedCrossRefGoogle Scholar
  36. 36.
    Nagaraj S, Nelson A, Youn JI, Cheng P, Quiceno D, Gabrilovich DI (2012) Antigen-specific CD4 + T cells regulate function of myeloid-derived suppressor cells in cancer via retrograde MHC class II signaling. Cancer Res 72(4):928–938PubMedCrossRefGoogle Scholar
  37. 37.
    Baniyash M (2004) TCR zeta-chain downregulation: curtailing an excessive inflammatory immune response. Nat Rev Immunol 4(9):675–687PubMedCrossRefGoogle Scholar
  38. 38.
    Walker LS, Sansom DM (2011) The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nat Rev Immunol 11(12):852–863PubMedCrossRefGoogle Scholar
  39. 39.
    Michels T, Shurin GV, Naiditch H, Sevko A, Umansky V, Shurin MR (2012) Paclitaxel promotes differentiation of myeloid-derived suppressor cells into dendritic cells in vitro in a TLR4-independent manner. J Immunotoxicol 9(3):292–300PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    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(2):226–232PubMedCrossRefGoogle Scholar
  41. 41.
    Naiditch H, Shurin MR, Shurin GV (2011) Targeting myeloid regulatory cells in cancer by chemotherapeutic agents. Immunol Res 50(2–3):276–285PubMedCrossRefGoogle Scholar
  42. 42.
    Mantovani A (2010) The growing diversity and spectrum of action of myeloid-derived suppressor cells. Eur J Immunol 40(12):3317–3320PubMedCrossRefGoogle Scholar
  43. 43.
    Del Vecchio M, Mortarini R, Tragni G, Di Guardo L, Bersani I, Di Tolla G, Agustoni F, Colonna V, Weber JS, Anichini A (2011) T-cell activation and maturation at tumor site associated with objective response to ipilimumab in metastatic melanoma. J Clin Oncol 29(32):783–788CrossRefGoogle Scholar
  44. 44.
    Mandruzzato S, Solito S, Falisi E, Francescato S, Chiarion-Sileni V, Mocellin S, Zanon A, Rossi CR, Nitti D, Bronte V, Zanovello P (2009) IL4Ralpha + myeloid-derived suppressor cell expansion in cancer patients. J Immunol 182(10):6562–6568PubMedCrossRefGoogle Scholar
  45. 45.
    Ohki S, Shibata M, Gonda K, Machida T, Shimura T, Nakamura I, Ohtake T, Koyama Y, Suzuki S, Ohto H, Takenoshita S (2012) Circulating myeloid-derived suppressor cells are increased and correlate to immune suppression, inflammation and hypoproteinemia in patients with cancer. Oncol Rep 28(2):453–458PubMedGoogle Scholar
  46. 46.
    Tarhini A (2012) Neoadjuvant ipilimumab in locally/regionally advanced melanoma: clinical outcome and immune monitoring. J Clin Oncol 30:Abstract 8553Google Scholar
  47. 47.
    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(9):702–710PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Wang XB, Giscombe R, Yan Z, Heiden T, Xu D, Lefvert AK (2002) Expression of CTLA-4 by human monocytes. Scand J Immunol 55(1):53–60PubMedCrossRefGoogle Scholar
  49. 49.
    Comin-Anduix B, Sazegar H, Chodon T, Matsunaga D, Jalil J, von Euw E, Escuin-Ordinas H, Balderas R, Chmielowski B, Gomez-Navarro J, Koya RC, Ribas A (2010) Modulation of cell signaling networks after CTLA4 blockade in patients with metastatic melanoma. PLoS ONE 5(9):e12711PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ (2008) Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother 58(1):49–59PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Ostrand-Rosenberg S, Sinha P (2009) Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 182(8):4499–4506PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Ji RR, Chasalow SD, Wang L, Hamid O, Schmidt H, Cogswell J, Alaparthy S, Berman D, Jure-Kunkel M, Siemers NO, Jackson JR, Shahabi V (2011) An immune-active tumor microenvironment favors clinical response to ipilimumab. Cancer Immunol Immunother 61(7):1019–1031PubMedCrossRefGoogle Scholar
  53. 53.
    Walter S, Weinschenk T, Stenzl A, Zdrojowy R, Pluzanska A, Szczylik C, Staehler M, Brugger W, Dietrich PY, Mendrzyk R, Hilf N, Schoor O, Fritsche J, Mahr A, Maurer D, Vass V, Trautwein C, Lewandrowski P, Flohr C, Pohla H, Stanczak JJ, Bronte V, Mandruzzato S, Biedermann T, Pawelec G, Derhovanessian E, Yamagishi H, Miki T, Hongo F, Takaha N, Hirakawa K, Tanaka H, Stevanovic S, Frisch J, Mayer-Mokler A, Kirner A, Rammensee HG, Reinhardt C, Singh-Jasuja H (2012) Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat Med 18(8):1254–1261PubMedCrossRefGoogle Scholar
  54. 54.
    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(10):1419–1430PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Christiane Meyer
    • 1
  • Laurène Cagnon
    • 1
  • Carla M. Costa-Nunes
    • 1
  • Petra Baumgaertner
    • 1
  • Nicole Montandon
    • 1
  • Loredana Leyvraz
    • 1
  • Olivier Michielin
    • 1
    • 2
  • Emanuela Romano
    • 2
  • Daniel E. Speiser
    • 1
    • 2
  1. 1.Ludwig Center for Cancer Research of the University of LausanneLausanneSwitzerland
  2. 2.Service of Medical Oncology, Department of OncologyLausanne University Hospital Center (CHUV)LausanneSwitzerland

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