Advertisement

Cancer Immunology, Immunotherapy

, Volume 67, Issue 12, pp 1919–1929 | Cite as

Myeloid-derived suppressor cells (MDSCs) in patients with solid tumors: considerations for granulocyte colony-stimulating factor treatment

  • Katerina Pilatova
  • Beatrix Bencsikova
  • Regina Demlova
  • Dalibor Valik
  • Lenka Zdrazilova-DubskaEmail author
Focussed Research Review
  • 364 Downloads

Abstract

Myeloid-derived suppressor cells (MDSCs) have been shown to contribute to tumor escape from host immune surveillance and to cancer progression by production of tumor-promoting soluble factors. Granulocyte colony-stimulating factor (G-CSF) is a principle cytokine controlling granulocyte number. Recombinant human G-CSF (rhG-CSF) has become the main therapeutic agent for the treatment of neutropenia and prophylaxis of febrile neutropenia in cancer patients. However, we show here that rhG-CSF triggers accumulation of granulocytic and monocytic subsets. Consequently, we discuss the pharmacological use of granulopoiesis stimulating factors not only in the context of febrile neutropenia but also from the perspective of MDSC-dependent and MDSC-independent mechanisms of immunosuppression and cancer angiogenesis.

Keywords

Myeloid-derived suppressor cells Granulocyte colony-stimulating factor Cancer Prophylaxis of febrile neutropenia CITIM 2017 

Abbreviations

ASCO

American Society of Clinical Oncology

ATRA

All-trans-retinoic acid

bFGF

Basic fibroblast growth factor

C/EBPβ

CCAAT/enhancer-binding protein beta

CARS

Compensatory anti-inflammatory response syndrome

CRP

C-reactive protein

CSF

Colony-stimulating factor

DAMP

Danger-associated molecular pattern

DC

Dendritic cell

EMA

European Medicines Agency

e-MDSC

Early myeloid-derived suppressor cell

FDA

Food and Drug Administration

FN

Febrile neutropenia

HMGB1

High-mobility group box 1

IRF

Interferon-regulatory factor

M-MDSC

Monocytic myeloid-derived suppressor cell

MMP

Matrix metallopeptidase

PAMP

Pathogen-associated molecular pattern

PDGF

Platelet-derived growth factor

PEG

Polyethylene glycol

PGE2

Prostaglandin E 2

PMN-MDSC

Polymorphonuclear myeloid-derived suppressor cell

rhG-CSF

Recombinant human granulocyte colony-stimulating factor

ROS

Reactive oxygen species

TAM

Tumor-associated macrophage

Notes

Author contributions

KP performed or supervised laboratory testing, contributed to data interpretation, prepared figures, and drafted the manuscript. BB referred patients and drafted the manuscript. RD contributed to data interpretation and drafted the manuscript. DV drafted and edited the manuscript. LZ-D conceived of the presented idea, designed the experiment and laboratory testing, and drafted and finalized the manuscript. All authors discussed the results and contributed to the final manuscript.

Funding

The work was supported by the Czech Ministry of Health (projects AZV 16-31966A and DRO 00209805) and the Czech Ministry of Education, Youth and Sports (projects LO1413, LM2015089, and LM2015090).

Compliance with ethical standards

Ethical approval

For pediatric patients treated by anti-cancer DC vaccines, academic clinical trial (EudraCT: 2014-003388-39) was approved by Czech national authority (State Institute for Drug Control).

Ethical standards

For adult cancer patients, the study was approved by Ethical Board of Masaryk Memorial Cancer Institute, Brno, Czech Republic.

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

262_2018_2166_MOESM1_ESM.pdf (444 kb)
Supplementary material 1 (PDF 444 KB)

References

  1. 1.
    Beeson PB (1946) Development of tolerance to typhoid bacterial pyrogen and its abolition by reticulo-endothelial blockade. Proc Soc Exp Biol Med 61:248–250CrossRefGoogle Scholar
  2. 2.
    Veglia F, Perego M, Gabrilovich D (2018) Myeloid-derived suppressor cells coming of age. Nat Immunol 19:108–119.  https://doi.org/10.1038/s41590-017-0022-x CrossRefPubMedGoogle Scholar
  3. 3.
    Manz MG, Boettcher S (2014) Emergency granulopoiesis. Nat Rev Immunol 14:302–314.  https://doi.org/10.1038/nri3660 CrossRefPubMedGoogle Scholar
  4. 4.
    Zhang H, Nguyen-Jackson H, Panopoulos AD, Li HS, Murray PJ, Watowich SS (2010) STAT3 controls myeloid progenitor growth during emergency granulopoiesis. Blood 116:2462–2471.  https://doi.org/10.1182/blood-2009-12-259630 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Talmadge JE, Gabrilovich DI (2013) History of myeloid-derived suppressor cells. Nat Rev Cancer 13:739–752.  https://doi.org/10.1038/nrc3581 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Shipp C, Speigl L, Janssen N, Martens A, Pawelec G (2016) A clinical and biological perspective of human myeloid-derived suppressor cells in cancer. Cell Mol Life Sci 73:4043–4061.  https://doi.org/10.1007/s00018-016-2278-y CrossRefPubMedGoogle Scholar
  7. 7.
    Najjar YG, Finke JH (2013) Clinical perspectives on targeting of myeloid derived suppressor cells in the treatment of cancer. Front Oncol 3:49.  https://doi.org/10.3389/fonc.2013.00049 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Peranzoni E, Zilio S, Marigo I, Dolcetti L, Zanovello P, Mandruzzato S, Bronte V (2010) Myeloid-derived suppressor cell heterogeneity and subset definition. Curr Opin Immunol 22:238–244.  https://doi.org/10.1016/j.coi.2010.01.021 CrossRefPubMedGoogle Scholar
  9. 9.
    Bronte V, Brandau S, Chen SH et al (2016) Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 7:12150.  https://doi.org/10.1038/ncomms12150 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    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 162:5728–5737PubMedPubMedCentralGoogle Scholar
  11. 11.
    Waight JD, Hu Q, Miller A, Liu S, Abrams SI (2011) Tumor-derived G-CSF facilitates neoplastic growth through a granulocytic myeloid-derived suppressor cell-dependent mechanism. PloS One 6:e27690.  https://doi.org/10.1371/journal.pone.0027690 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Adib-Conquy M, Cavaillon JM (2009) Compensatory anti-inflammatory response syndrome. Thromb Haemost 101:36–47CrossRefGoogle Scholar
  13. 13.
    Pena OM, Pistolic J, Raj D, Fjell CD, Hancock RE (2011) Endotoxin tolerance represents a distinctive state of alternative polarization (M2) in human mononuclear cells. J Immunol 186:7243–7254.  https://doi.org/10.4049/jimmunol.1001952 CrossRefPubMedGoogle Scholar
  14. 14.
    Sakuta T, Matsushita K, Yamaguchi N et al (2001) Enhanced production of vascular endothelial growth factor by human monocytic cells stimulated with endotoxin through transcription factor SP-1. J Med Microbiol 50:233–237.  https://doi.org/10.1099/0022-1317-50-3-233 CrossRefPubMedGoogle Scholar
  15. 15.
    Corzo CA, Condamine T, Lu L et al (2010) HIF-1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med 207:2439–2453.  https://doi.org/10.1084/jem.20100587 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Strauss L, Sangaletti S, Consonni FM et al (2015) RORC1 regulates tumor-promoting “emergency” granulo-monocytopoiesis. Cancer Cell 28:253–269.  https://doi.org/10.1016/j.ccell.2015.07.006 CrossRefPubMedGoogle Scholar
  17. 17.
    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.  https://doi.org/10.1158/0008-5472.CAN-08-1921 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Solito S, Falisi E, Diaz-Montero CM et al (2011) A human promyelocytic-like population is responsible for the immune suppression mediated by myeloid-derived suppressor cells. Blood 118:2254–2265.  https://doi.org/10.1182/blood-2010-12-325753 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Umansky V, Sevko A (2013) Tumor microenvironment and myeloid-derived suppressor cells. Cancer Microenviron 6:169–177.  https://doi.org/10.1007/s12307-012-0126-7 CrossRefPubMedGoogle Scholar
  20. 20.
    Yan D, Yang Q, Shi M, Zhong L, Wu C, Meng T, Yin H, Zhou J (2013) Polyunsaturated fatty acids promote the expansion of myeloid-derived suppressor cells by activating the JAK/STAT3 pathway. Eur J Immunol 43:2943–2955.  https://doi.org/10.1002/eji.201343472 CrossRefPubMedGoogle Scholar
  21. 21.
    Abrams SI, Waight JD (2012) Identification of a G-CSF-granulocytic MDSC axis that promotes tumor progression. Oncoimmunology 1:550–551CrossRefGoogle Scholar
  22. 22.
    Allen MD, Jones LJ (2015) The role of inflammation in progression of breast cancer: friend or foe? (Review). Int J Oncol 47:797–805.  https://doi.org/10.3892/ijo.2015.3075 CrossRefPubMedGoogle Scholar
  23. 23.
    Dorhoi A, Du Plessis N (2017) Monocytic myeloid-derived suppressor cells in chronic infections. Front Immunol 8:1895.  https://doi.org/10.3389/fimmu.2017.01895 CrossRefPubMedGoogle Scholar
  24. 24.
    Mao Y, Poschke I, Wennerberg E et al (2013) Melanoma-educated CD14+ cells acquire a myeloid-derived suppressor cell phenotype through COX-2-dependent mechanisms. Cancer Res 73:3877–3887.  https://doi.org/10.1158/0008-5472.CAN-12-4115 CrossRefPubMedGoogle Scholar
  25. 25.
    Vignali DA, Collison LW, Workman CJ (2008) How regulatory T cells work. Nat Rev Immunol 8:523–532.  https://doi.org/10.1038/nri2343 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Markowitz J, Wang J, Vangundy Z et al (2017) Nitric oxide mediated inhibition of antigen presentation from DCs to CD4(+) T cells in cancer and measurement of STAT1 nitration. Sci Rep 7:15424.  https://doi.org/10.1038/s41598-017-14970-0 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Cohen PA, Ko JS, Storkus WJ et al (2012) Myeloid-derived suppressor cells adhere to physiologic STAT3- vs STAT5-dependent hematopoietic programming, establishing diverse tumor-mediated mechanisms of immunologic escape. Immunol Investig 41:680–710.  https://doi.org/10.3109/08820139.2012.703745 CrossRefGoogle Scholar
  28. 28.
    Shojaei F, Ferrara N (2008) Refractoriness to antivascular endothelial growth factor treatment: role of myeloid cells. Cancer Res 68:5501–5504.  https://doi.org/10.1158/0008-5472.CAN-08-0925 CrossRefPubMedGoogle Scholar
  29. 29.
    Ben-Baruch A (2012) The tumor-promoting flow of cells into, within and out of the tumor site: regulation by the inflammatory axis of tnfalpha and chemokines. Cancer Microenviron 5:151–164.  https://doi.org/10.1007/s12307-011-0094-3 CrossRefPubMedGoogle Scholar
  30. 30.
    Watari K, Asano S, Shirafuji N, Kodo H, Ozawa K, Takaku F, Kamachi S (1989) Serum granulocyte colony-stimulating factor levels in healthy volunteers and patients with various disorders as estimated by enzyme immunoassay. Blood 73:117–122PubMedGoogle Scholar
  31. 31.
    Lord BI, Bronchud MH, Owens S, Chang J, Howell A, Souza L, Dexter TM (1989) The kinetics of human granulopoiesis following treatment with granulocyte colony-stimulating factor in vivo. Proc Natl Acad Sci USA 86:9499–9503CrossRefGoogle Scholar
  32. 32.
    Sarvi F, Arabahmadi M, Alleyassin A, Aghahosseini M, Ghasemi M (2017) Effect of increased endometrial thickness and implantation rate by granulocyte colony-stimulating factor on unresponsive thin endometrium in fresh in vitro fertilization cycles: a randomized clinical trial. Obstet Gynecol Int. 2017:3596079.  https://doi.org/10.1155/2017/3596079 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Huang X, Liu Y, Bai S, Peng L, Zhang B, Lu H (2017) Granulocyte colony stimulating factor therapy for stroke: a pairwise meta-analysis of randomized controlled trial. PloS One 12:e0175774.  https://doi.org/10.1371/journal.pone.0175774 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Kotzur T, Benavides-Garcia R, Mecklenburg J, Sanchez JR, Reilly M, Hermann BP (2017) Granulocyte colony-stimulating factor (G-CSF) promotes spermatogenic regeneration from surviving spermatogonia after high-dose alkylating chemotherapy. Reprod Biol Endocrinol 15:7.  https://doi.org/10.1186/s12958-016-0226-1 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Dale DC (2002) Colony-stimulating factors for the management of neutropenia in cancer patients. Drugs 62(Suppl 1):1–15CrossRefGoogle Scholar
  36. 36.
    Lyman GH, Kuderer NM, Crawford J, Wolff DA, Culakova E, Poniewierski MS, Dale DC (2011) Predicting individual risk of neutropenic complications in patients receiving cancer chemotherapy. Cancer 117:1917–1927.  https://doi.org/10.1002/cncr.25691 CrossRefGoogle Scholar
  37. 37.
    Yang BB, Kido A (2011) Pharmacokinetics and pharmacodynamics of pegfilgrastim. Clin Pharmacokinet 50:295–306.  https://doi.org/10.2165/11586040-000000000-00000 CrossRefPubMedGoogle Scholar
  38. 38.
    Kuwabara T, Kobayashi S, Sugiyama Y (1996) Pharmacokinetics and pharmacodynamics of a recombinant human granulocyte colony-stimulating factor. Drug Metab Rev 28:625–658.  https://doi.org/10.3109/03602539608994020 CrossRefPubMedGoogle Scholar
  39. 39.
    Carulli G (1997) Effects of recombinant human granulocyte colony-stimulating factor administration on neutrophil phenotype and functions. Haematologica 82:606–616PubMedGoogle Scholar
  40. 40.
    Tigue CC, McKoy JM, Evens AM, Trifilio SM, Tallman MS, Bennett CL (2007) Granulocyte-colony stimulating factor administration to healthy individuals and persons with chronic neutropenia or cancer: an overview of safety considerations from the Research on Adverse Drug Events and Reports project. Bone Marrow Transplant 40:185–192.  https://doi.org/10.1038/sj.bmt.1705722 CrossRefPubMedGoogle Scholar
  41. 41.
    Socie G, Mary JY, Schrezenmeier H et al (2007) Granulocyte-stimulating factor and severe aplastic anemia: a survey by the European Group for Blood and Marrow Transplantation (EBMT). Blood 109:2794–2796.  https://doi.org/10.1182/blood-2006-07-034272 CrossRefPubMedGoogle Scholar
  42. 42.
    Rosenberg PS, Alter BP, Bolyard AA et al (2006) The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy. Blood 107:4628–4635.  https://doi.org/10.1182/blood-2005-11-4370 CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Hershman D, Neugut AI, Jacobson JS, Wang J, Tsai WY, McBride R, Bennett CL, Grann VR (2007) Acute myeloid leukemia or myelodysplastic syndrome following use of granulocyte colony-stimulating factors during breast cancer adjuvant chemotherapy. J Natl Cancer Inst 99:196–205.  https://doi.org/10.1093/jnci/djk028 CrossRefPubMedGoogle Scholar
  44. 44.
    Kim CH (2010) Homeostatic and pathogenic extramedullary hematopoiesis. J Blood Med 1:13–19.  https://doi.org/10.2147/JBM.S7224 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Platzbecker U, Prange-Krex G, Bornhauser M et al (2001) Spleen enlargement in healthy donors during G-CSF mobilization of PBPCs. Transfusion 41:184–189CrossRefGoogle Scholar
  46. 46.
    Picardi M, De Rosa G, Selleri C, Scarpato N, Soscia E, Martinelli V, Ciancia R, Rotoli B (2003) Spleen enlargement following recombinant human granulocyte colony-stimulating factor administration for peripheral blood stem cell mobilization. Haematologica 88:794–800PubMedGoogle Scholar
  47. 47.
    Shojaei F, Wu X, Qu X, Kowanetz M, Yu L, Tan M, Meng YG, Ferrara N (2009) G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models. Proc Natl Acad Sci USA 106:6742–6747.  https://doi.org/10.1073/pnas.0902280106 CrossRefPubMedGoogle Scholar
  48. 48.
    Luyckx A, Schouppe E, Rutgeerts O et al. (2012) G-CSF stem cell mobilization in human donors induces polymorphonuclear and mononuclear myeloid-derived suppressor cells. Clin Immunol 143:83–87.  https://doi.org/10.1016/j.clim.2012.01.011 CrossRefPubMedGoogle Scholar
  49. 49.
    Morris KT, Khan H, Ahmad A, Weston LL, Nofchissey RA, Pinchuk IV, Beswick EJ (2014) G-CSF and G-CSFR are highly expressed in human gastric and colon cancers and promote carcinoma cell proliferation and migration. Br J Cancer 110:1211–1220.  https://doi.org/10.1038/bjc.2013.822 CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Aliper AM, Frieden-Korovkina VP, Buzdin A, Roumiantsev SA, Zhavoronkov A (2014) A role for G-CSF and GM-CSF in nonmyeloid cancers. Cancer Med 3:737–746.  https://doi.org/10.1002/cam4.239 CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Gay AN, Chang S, Rutland L, Yu L, Byeseda S, Naik-Mathuria B, Cass DL, Russell H, Olutoye OO (2008) Granulocyte colony stimulating factor alters the phenotype of neuroblastoma cells: implications for disease-free survival of high-risk patients. J Pediatr Surg 43:837–842.  https://doi.org/10.1016/j.jpedsurg.2007.12.024 CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Rutella S, Zavala F, Danese S, Kared H, Leone G (2005) Granulocyte colony-stimulating factor: a novel mediator of T cell tolerance. J Immunol 175:7085–7091CrossRefGoogle Scholar
  53. 53.
    Anderlini P (2009) Effects and safety of granulocyte colony-stimulating factor in healthy volunteers. Curr Opin Hematol 16:35–40.  https://doi.org/10.1097/MOH.0b013e328319913c CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Pilatova K, Greplova K, Demlova R, Bencsikova B, Klement GL, Zdrazilova-Dubska L (2013) Role of platelet chemokines, PF-4 and CTAP-III, in cancer biology. J Hematol Oncol 6:42.  https://doi.org/10.1186/1756-8722-6-42 CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    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 61:1155–1167.  https://doi.org/10.1007/s00262-012-1294-5 CrossRefPubMedGoogle Scholar
  56. 56.
    Lyman G, Reiner M, Morrow P, Crawford J (2015) The effect of filgrastim or pegfilgrastim on survival outcomes of patients with cancer receiving myelosuppressive chemotherapy. Ann Oncol 26:1452–1458.  https://doi.org/10.1093/annonc/mdv174 CrossRefPubMedGoogle Scholar
  57. 57.
    Staar S, Rudat V, Stuetzer H, Dietz A, Volling P, Schroeder M, Flentje M, Eckel HE, Mueller RP (2001) Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy—results of a multicentric randomized German trial in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 50:1161–1171CrossRefGoogle Scholar
  58. 58.
    Gutschalk CM, Herold-Mende CC, Fusenig NE, Mueller MM (2006) Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor promote malignant growth of cells from head and neck squamous cell carcinomas in vivo. Cancer Res 66:8026–8036.  https://doi.org/10.1158/0008-5472.CAN-06-0158 CrossRefPubMedGoogle Scholar
  59. 59.
    Fishman ML, Kumar A, Davis S, Shimp W, Hrushesky WJ (2012) Guideline-based peer-to-peer consultation optimizes pegfilgrastim use with no adverse clinical consequences. J Oncol Pract 8:e14s–e17s.  https://doi.org/10.1200/JOP.2012.000540 CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Smith TJ, Bohlke K, Lyman GH et al. (2015) Recommendations for the use of wbc growth factors: american society of clinical oncology clinical practice guideline update. J Clin Oncol 33:3199–3212.  https://doi.org/10.1200/JCO.2015.62.3488 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Katerina Pilatova
    • 1
    • 2
    • 3
  • Beatrix Bencsikova
    • 2
    • 4
  • Regina Demlova
    • 2
    • 3
    • 5
  • Dalibor Valik
    • 1
    • 2
    • 3
  • Lenka Zdrazilova-Dubska
    • 1
    • 2
    • 3
    Email author
  1. 1.Department of Laboratory MedicineMasaryk Memorial Cancer InstituteBrnoCzech Republic
  2. 2.RECAMO, Masaryk Memorial Cancer InstituteBrnoCzech Republic
  3. 3.Department of Pharmacology, Medical FacultyMasaryk UniversityBrnoCzech Republic
  4. 4.Department of Comprehensive Cancer CareMasaryk Memorial Cancer InstituteBrnoCzech Republic
  5. 5.Clinical Trial UnitMasaryk Memorial Cancer InstituteBrnoCzech Republic

Personalised recommendations