Skip to main content

Advertisement

SpringerLink
Log in

Myeloid-derived suppressor cells and their role in CTLA-4 blockade therapy

  • Focussed Research Review
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Immune checkpoints are a series of inhibitory pathways that are crucial for modulating the intensity and duration of immune response. Among these checkpoints, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) has been shown to be a key regulator of the early activation of naïve and memory T cells. Immune checkpoint blockade is emerging as one of the most promising therapeutic approaches directed toward the activation of the immune response against tumors. The first of these therapies that has been FDA approved is ipilimumab, a fully human monoclonal antibody that blocks CTLA-4. The in cis effects that CTLA-4 blockade has on T cells have been properly described, but there are still questions to be answered regarding the indirect or in trans effects. One of the alternative cellular populations that may play a role in the outcome of CTLA-4 blockade therapy is myeloid-derived suppressor cells (MDSCs), which have recently been associated with clinical outcome in advanced melanoma. In addition to this, MDSCs have been shown to be decreased in number and functional potential after treatment with ipilimumab. A better clarification of what effects CTLA-4 blockade may have on these cellular populations is likely to provide insights on possible predictive biomarkers for CTLA-4 blockade therapy.

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
Fig. 2

Similar content being viewed by others

References

  1. June CH, Ledbetter JA, Gillespie MM, Lindsten T, Thompson CB (1987) T-cell proliferation involving the CD28 pathway is associated with cyclosporine-resistant interleukin 2 gene expression. Mol Cell Biol 7(12):4472–4481

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Thompson CB, Lindsten T, Ledbetter JA, Kunkel SL, Young HA, Emerson SG, Leiden JM, June CH (1989) CD28 activation pathway regulates the production of multiple T-cell-derived lymphokines/cytokines. Proc Natl Acad Sci USA 86(4):1333–1337

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG, Golstein P (1987) A new member of the immunoglobulin superfamily–CTLA-4. Nature 328(6127):267–270

    Article  CAS  PubMed  Google Scholar 

  4. Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA (1991) CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med 174(3):561–569

    Article  CAS  PubMed  Google Scholar 

  5. Teft WA, Kirchhof MG, Madrenas J (2006) A molecular perspective of CTLA-4 function. Annu Rev Immunol 24:65–97

    Article  CAS  PubMed  Google Scholar 

  6. Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, Thompson CB, Griesser H, Mak TW (1995) Lymphoproliferative disorders with early lethality in mice deficient in CTLA-4. Science 270(5238):985–988

    Article  CAS  PubMed  Google Scholar 

  7. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH (1995) Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3(5):541–547

    Article  CAS  PubMed  Google Scholar 

  8. Pioli C, Gatta L, Ubaldi V, Doria G (2000) Inhibition of IgG1 and IgE production by stimulation of the B cell CTLA-4 receptor. J Immunol 165(10):5530–5536

    Article  CAS  PubMed  Google Scholar 

  9. 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):53–60

    Article  CAS  PubMed  Google Scholar 

  10. Wang XB, Fan ZZ, Anton D, Vollenhoven AV, Ni ZH, Chen XF, Lefvert AK (2011) CTLA4 is expressed on mature dendritic cells derived from human monocytes and influences their maturation and antigen presentation. BMC Immunol 12:21

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Pistillo MP, Tazzari PL, Palmisano GL, Pierri I, Bolognesi A, Ferlito F, Capanni P, Polito L, Ratta M, Pileri S, Piccioli M, Basso G, Rissotto L, Conte R, Gobbi M, Stirpe F, Ferrara GB (2003) CTLA-4 is not restricted to the lymphoid cell lineage and can function as a target molecule for apoptosis induction of leukemic cells. Blood 101(1):202–209

    Article  CAS  PubMed  Google Scholar 

  12. Linsley PS, Bradshaw J, Greene J, Peach R, Bennett KL, Mittler RS (1996) Intracellular trafficking of CTLA-4 and focal localization towards sites of TCR engagement. Immunity 4(6):535–543

    Article  CAS  PubMed  Google Scholar 

  13. Egen JG, Allison JP (2002) Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity 16(1):23–35

    Article  CAS  PubMed  Google Scholar 

  14. Walker LS, Sansom DM (2011) The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nat Rev Immunol 11(12):852–863

    CAS  PubMed  Google Scholar 

  15. Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, Mak TW, Sakaguchi S (2000) Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 192(2):303–310

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Qureshi OS, Zheng Y, Nakamura K, Attridge K, Manzotti C, Schmidt EM, Baker J, Jeffery LE, Kaur S, Briggs Z, Hou TZ, Futter CE, Anderson G, Walker LS, Sansom DM (2011) Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 332(6029):600–603

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Topalian SL, Drake CG, Pardoll DM (2012) Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol 24(2):207–212

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Nishimura H, Nose M, Hiai H, Minato N, Honjo T (1999) Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11(2):141–151

    Article  CAS  PubMed  Google Scholar 

  19. Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, Sasayama S, Mizoguchi A, Hiai H, Minato N, Honjo T (2001) Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291(5502):319–322

    Article  CAS  PubMed  Google Scholar 

  20. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T (2000) Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192(7):1027–1034

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R, Greenfield EA, Bourque K, Boussiotis VA, Carter LL, Carreno BM, Malenkovich N, Nishimura H, Okazaki T, Honjo T, Sharpe AH, Freeman GJ (2001) PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2(3):261–268

    Article  CAS  PubMed  Google Scholar 

  22. Lee PP, Yee C, Savage PA, Fong L, Brockstedt D, Weber JS, Johnson D, Swetter S, Thompson J, Greenberg PD, Roederer M, Davis MM (1999) Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients. Nat Med 5(6):677–685

    Article  CAS  PubMed  Google Scholar 

  23. Clark WH Jr, Elder DE, Guerry Dt, Braitman LE, Trock BJ, Schultz D, Synnestvedt M, Halpern AC (1989) Model predicting survival in stage I melanoma based on tumor progression. J Natl Cancer Inst 81(24):1893–1904

    Article  PubMed  Google Scholar 

  24. Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, Xu Y, Li YW, Tang ZY (2007) Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 25(18):2586–2593

    Article  PubMed  Google Scholar 

  25. Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN, Rubin SC, Coukos G (2003) Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348(3):203–213

    Article  CAS  PubMed  Google Scholar 

  26. Dudley ME, Rosenberg SA (2003) Adoptive-cell-transfer therapy for the treatment of patients with cancer. Nat Rev Cancer 3(9):666–675

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. 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):2350–2360

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Read S, Malmstrom V, Powrie F (2000) Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med 192(2):295–302

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, Nomura T, Sakaguchi S (2008) CTLA-4 control over Foxp3+ regulatory T cell function. Science 322(5899):271–275

    Article  CAS  PubMed  Google Scholar 

  30. 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):711–723

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Callahan MK, Wolchok JD (2013) At the bedside: CTLA-4- and PD-1-blocking antibodies in cancer immunotherapy. J Leukoc Biol 94(1):41–53

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Blank CU (2014) The perspective of immunotherapy: new molecules and new mechanisms of action in immune modulation. Curr Opin Oncol 26(2):204–214

  33. Kavanagh B, O’Brien S, Lee D, Hou Y, Weinberg V, Rini B, Allison JP, Small EJ, Fong L (2008) CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion. Blood 112(4):1175–1183

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Weber JS, Hamid O, Chasalow SD, Wu DY, Parker SM, Galbraith S, Gnjatic S, Berman D (2012) Ipilimumab increases activated T cells and enhances humoral immunity in patients with advanced melanoma. J Immunother 35(1):89–97

    Article  CAS  PubMed  Google Scholar 

  36. Fu T, He Q, Sharma P (2011) The ICOS/ICOSL pathway is required for optimal antitumor responses mediated by anti-CTLA-4 therapy. Cancer Res 71(16):5445–5454

    Article  CAS  PubMed  Google Scholar 

  37. Fan X, Quezada SA, Sepulveda MA, Sharma P, Allison JP (2014) Engagement of the ICOS pathway markedly enhances efficacy of CTLA-4 blockade in cancer immunotherapy. J Exp Med 211(4):715–725

    Article  CAS  PubMed  Google Scholar 

  38. Ng Tang D, Shen Y, Sun J, Wen S, Wolchok JD, Yuan J, Allison JP, Sharma P (2013) Increased frequency of ICOS+ CD4 T cells as a pharmacodynamic biomarker for anti-CTLA-4 therapy. Cancer Immunol Res 1(4):229–234

    Article  PubMed  Google Scholar 

  39. Simpson TR, Li F, Montalvo-Ortiz W, Sepulveda MA, Bergerhoff K, Arce F, Roddie C, Henry JY, Yagita H, Wolchok JD, Peggs KS, Ravetch JV, Allison JP, Quezada SA (2013) Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J Exp Med 210(9):1695–1710

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Laurent S, Queirolo P, Boero S, Salvi S, Piccioli P, Boccardo S, Minghelli S, Morabito A, Fontana V, Pietra G, Carrega P, Ferrari N, Tosetti F, Chang LJ, Mingari MC, Ferlazzo G, Poggi A, Pistillo MP (2013) The engagement of CTLA-4 on primary melanoma cell lines induces antibody-dependent cellular cytotoxicity and TNF-alpha production. J Transl Med 11:108

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Gabrilovich DI, Bronte V, Chen SH, Colombo MP, Ochoa A, Ostrand-Rosenberg S, Schreiber H (2007) The terminology issue for myeloid-derived suppressor cells. Cancer Res 67(1):425 author reply 426

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Poschke I, Kiessling R (2012) On the armament and appearances of human myeloid-derived suppressor cells. Clin Immunol 144(3):250–268

    Article  CAS  PubMed  Google Scholar 

  43. 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):4335–4345

    Article  CAS  PubMed  Google Scholar 

  44. Mao Y, Poschke I, Wennerberg E, Pico de Coana Y, Egyhazi Brage S, Schultz I, Hansson J, Masucci G, Lundqvist A, Kiessling R (2013) Melanoma-educated CD14+ cells acquire a myeloid-derived suppressor cell phenotype through COX-2-dependent mechanisms. Cancer Res 73(13):3877–3887

    Article  CAS  PubMed  Google Scholar 

  45. Weide B, Martens A, Zelba H, Stutz C, Derhovanessian E, Di Giacomo AM, Maio M, Sucker A, Schilling B, Schadendorf D, Buttner P, Garbe C, Pawelec G (2013) Myeloid-derived suppressor cells predict survival of advanced melanoma patients: comparison with regulatory T cells and NY-ESO-1- or Melan-A-specific T cells. Clin Cancer Res 20(6):1601–1609

    Article  PubMed  Google Scholar 

  46. Schilling B, Sucker A, Griewank K, Zhao F, Weide B, Gorgens A, Giebel B, Schadendorf D, Paschen A (2013) Vemurafenib reverses immunosuppression by myeloid derived suppressor cells. Int J Cancer 133(7):1653–1663

    Article  CAS  PubMed  Google Scholar 

  47. Pico de Coaña Y, Gentilcore G, Mao Y, Nyström M, Hansson J, Masucci GV, Kiessling R (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(3):158–162

    Article  PubMed  Google Scholar 

  48. 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):2546–2553

    Article  CAS  PubMed  Google Scholar 

  49. Meyer C, Cagnon L, Costa-Nunes CM, Baumgaertner P, Montandon N, Leyvraz L, Michielin O, Romano E, Speiser DE (2014) Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab. Cancer Immunol Immunother 63(3):247–257

    Article  CAS  PubMed  Google Scholar 

  50. Tarhini AA, Edington H, Butterfield LH, Lin Y, Shuai Y, Tawbi H, Sander C, Yin Y, Holtzman M, Johnson J, Rao UN, Kirkwood JM (2014) Immune monitoring of the circulation and the tumor microenvironment in patients with regionally advanced melanoma receiving neoadjuvant ipilimumab. PLoS ONE 9(2):e87705

    Article  PubMed Central  PubMed  Google Scholar 

  51. Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM (2005) Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res 11(18):6713–6721

    Article  CAS  PubMed  Google Scholar 

  52. Kodumudi KN, Woan K, Gilvary DL, Sahakian E, Wei S, Djeu JY (2010) A novel chemoimmunomodulating property of docetaxel: suppression of myeloid-derived suppressor cells in tumor bearers. Clin Cancer Res 16(18):4583–4594

    Article  CAS  PubMed  Google Scholar 

  53. Ko JS, Zea AH, Rini BI, Ireland JL, Elson P, Cohen P, Golshayan A, Rayman PA, Wood L, Garcia J, Dreicer R, Bukowski R, Finke JH (2009) Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res 15(6):2148–2157

    Article  CAS  PubMed  Google Scholar 

  54. Kitano S, Tsuji T, Liu C, Hirschhorn-Cymerman D, Kyi C, Mu Z, Allison JP, Gnjatic S, Yuan JD, Wolchok JD (2013) Enhancement of tumor-reactive cytotoxic CD4 T cell responses after ipilimumab treatment in four advanced melanoma patients. Cancer Immunol Res 1:235–244

    Article  CAS  PubMed  Google Scholar 

  55. 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):16723–16728

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Raja Choudhury for revising the manuscript. This study was supported by Grants from The Knut and Alice Wallenberg Foundation, The Swedish Cancer Society (12-0598 Cancerfonden), The Stockholm Cancer Society (121103 Cancerföreningen, Radiumhemmets Forskningsfonder), The Swedish Medical Research Council (K2011-66X-15387-07-3VR) and an ALF-Project Grant from Stockholm City Council (20110070 ALF-Medicin-2012).

Conflict of interest

Rolf Kiessling and Johan Hansson have received fees for lectures and other educational activities from Bristol-Myers Squibb. The remaining authors have no conflict of interests.

Author information

Authors and Affiliations

  1. Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska University Hospital, Karolinska Institutet, R08:01, 171 76, Stockholm, Sweden

    Yago Pico de Coaña, Giuseppe Masucci, Johan Hansson & Rolf Kiessling

Authors
  1. Yago Pico de Coaña
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Giuseppe Masucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Johan Hansson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rolf Kiessling
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yago Pico de Coaña.

Additional information

This paper is a Focussed Research Review based on a presentation given at the 19th Danish Cancer Society Symposium in Copenhagen, Denmark, 23rd–25th September 2013, on the topic “Immunotherapy of Cancer—Present Status and Future Promise”. It is a part of a CII series of Focussed Research Reviews and meeting report.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pico de Coaña, Y., Masucci, G., Hansson, J. et al. Myeloid-derived suppressor cells and their role in CTLA-4 blockade therapy. Cancer Immunol Immunother 63, 977–983 (2014). https://doi.org/10.1007/s00262-014-1570-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-014-1570-7

Keywords

Search

Navigation