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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

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Abstract

Myeloid-derived suppressor cells (MDSC) are believed to play a role in immune suppression and subsequent failure of T cells to mount an efficient anti-tumor response, by employing both direct T-cell inhibition as well as induction of regulatory T cells (Tregs). Investigating the frequency and function of immune suppressive cell subsets in the peripheral blood of 41 patients with prostate cancer (PC) and 36 healthy donors (HD) showed a significant increase in circulating CD14+ HLA-DRlow/neg monocytic MDSC (M-MDSC) and Tregs in patients with PC compared to HD. Furthermore, M-MDSC frequencies correlated positively with Treg levels. In vitro proliferation assay with autologous T cells confirmed M-MDSC-mediated T-cell suppression, and intracellular staining of immune suppressive enzyme iNOS revealed a higher expression in M-MDSC from patients with PC. Increased frequencies of M-MDSC correlated with known negative prognostic markers in patients with PC including elevated levels of lactate dehydrogenase and prostate-specific antigen. Accordingly, high levels of M-MDSC were associated with a shorter median overall survival. Our data strongly suggest that M-MDSC, possibly along with Tregs, play a role in establishing an immune suppressive environment in patients with PC. Moreover, correlation of M-MDSC frequency with known prognostic markers and the observed impact on OS could reflect a possible role in tumor progression. Further insight into the generation and function of MDSC and their interplay with Tregs and other cell types may suggest ways to tackle their induction and/or function to improve immunological tumor control.

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References

  1. Klotz L, Zhang L, Lam A et al (2010) Clinical results of long-term follow-up of a large, active surveillance cohort with localized prostate cancer. J Clin Oncol 28:126–131. doi:10.1200/JCO.2009.24.2180

    Article  PubMed  Google Scholar 

  2. Carvalhal GF, Daudi SN, Kan D et al (2010) Correlation between serum prostate-specific antigen and cancer volume in prostate glands of different sizes. Urology 76:1072–1076. doi:10.1016/j.urology.2009.11.056

    Article  PubMed  PubMed Central  Google Scholar 

  3. Small EJ, Schellhammer PF, Higano CS et al (2006) Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 24:3089–3094. doi:10.1200/JCO.2005.04.5252

    Article  PubMed  CAS  Google Scholar 

  4. Kantoff PW, Schuetz TJ, Blumenstein Ba et al (2010) Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol 28:1099–1105. doi:10.1200/JCO.2009.25.0597

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. Rigamonti N, Bellone M (2012) Prostate cancer, tumor immunity and a renewed sense of optimism in immunotherapy. Cancer Immunol Immunother 61:453–468. doi:10.1007/s00262-012-1216-6

    Article  PubMed  CAS  Google Scholar 

  6. Filipazzi P, Valenti R, Huber V 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. doi:10.1200/JCO.2006.08.5829

    Article  PubMed  CAS  Google Scholar 

  7. Poschke I, Kiessling R (2012) On the armament and appearances of human myeloid-derived suppressor cells. Clin Immunol 144:250–268. doi:10.1016/j.clim.2012.06.003

    Article  PubMed  CAS  Google Scholar 

  8. Bronte V, Zanovello P (2005) Regulation of immune responses by l-arginine metabolism. Nat Rev Immunol 5:641–654. doi:10.1038/nri1668

    Article  PubMed  CAS  Google Scholar 

  9. Habibi D, Jalili RB, Forouzandeh F et al (2010) High expression of IMPACT protein promotes resistance to indoleamine 2,3-dioxygenase-induced cell death. J Cell Physiol 225:196–205. doi:10.1002/jcp.22220

    Article  PubMed  CAS  Google Scholar 

  10. Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9:162–174. doi:10.1038/nri2506

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  11. Beyer M, Schultze JL (2006) Regulatory T cells in cancer. Blood 108:804–811. doi:10.1182/blood-2006-02-002774

    Article  PubMed  CAS  Google Scholar 

  12. Gustafson MP, Lin Y, New KC et al (2010) Systemic immune suppression in glioblastoma: the interplay between CD14+ HLA-DRlo/neg monocytes, tumor factors, and dexamethasone. Neuro Oncol 12:631–644. doi:10.1093/neuonc/noq001

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  13. Kalathil S, Lugade Aa, Miller A et al (2013) Higher Frequencies of GARP+ CTLA-4+ Foxp3+ T regulatory cells and myeloid-derived suppressor cells in hepatocellular carcinoma patients are associated with impaired T-Cell functionality. Cancer Res 73:2435–2444. doi:10.1158/0008-5472.CAN-12-3381

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  14. Ko JS, Zea AH, Rini BI et al (2009) Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res 15:2148–2157. doi:10.1158/1078-0432.CCR-08-1332

    Article  PubMed  CAS  Google Scholar 

  15. Hoechst B, Gamrekelashvili J, Manns MP et al (2011) Plasticity of human Th17 cells and iTregs is orchestrated by different subsets of myeloid cells. Blood 117:6532–6541. doi:10.1182/blood-2010-11-317321

    Article  PubMed  CAS  Google Scholar 

  16. Liu W, Putnam AL, Xu-Yu Z et al (2006) CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 203:1701–1711. doi:10.1084/jem.20060772

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Riley CH, Jensen MK, Brimnes MK et al (2011) Increase in circulating CD4+CD25+Foxp3+ T cells in patients with Philadelphia-negative chronic myeloproliferative neoplasms during treatment with IFN-α. Blood 118:2170–2173. doi:10.1182/blood-2011-03-340992

    Article  PubMed  Google Scholar 

  18. Halabi S, Lin C-Y, Kelly WK et al (2014) Updated prognostic model for predicting overall survival in first-line chemotherapy for patients with metastatic castration-resistant prostate cancer. J Clin Oncol 32:671–677. doi:10.1200/JCO.2013.52.3696

    Article  PubMed  Google Scholar 

  19. Bronte V, Wang M, Overwijk WW et al (1998) Apoptotic death of CD8+ T lymphocytes after immunization: induction of a suppressive population of Mac-1+/Gr-1+ cells. J Immunol 161:5313–5320

    PubMed  CAS  PubMed Central  Google Scholar 

  20. Walter S, Weinschenk T, Stenzl A et al (2012) Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat Med 18:1254–1261. doi:10.1038/nm.2883

    Article  PubMed  CAS  Google Scholar 

  21. Vuk-Pavlović S, Bulur Pa, Lin Y et al (2010) Immunosuppressive CD14+ HLA-DRlow/- monocytes in prostate cancer. Prostate 70:443–455. doi:10.1002/pros.21078

    PubMed  PubMed Central  Google Scholar 

  22. Brusa D, Simone M, Gontero P et al (2013) Circulating immunosuppressive cells of prostate cancer patients before and after radical prostatectomy: profile comparison. Int J Urol 20:971–978. doi:10.1111/iju

    PubMed  CAS  Google Scholar 

  23. Filipazzi P, Huber V, Rivoltini L (2012) Phenotype, function and clinical implications of myeloid-derived suppressor cells in cancer patients. Cancer Immunol Immunother 61:255–263. doi:10.1007/s00262-011-1161-9

    Article  PubMed  CAS  Google Scholar 

  24. Kotsakis A, Harasymczuk M, Schilling B et al (2012) Myeloid-derived suppressor cell measurements in fresh and cryopreserved blood samples. J Immunol Methods 381:14–22. doi:10.1016/j.jim.2012.04.004

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Poschke I, Mougiakakos D, Hansson J et al (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. doi:10.1158/0008-5472.CAN-09-3767

    Article  PubMed  CAS  Google Scholar 

  26. Ramachandran IR, Martner A, Pisklakova A et al (2013) Myeloid-derived suppressor cells regulate growth of multiple myeloma by inhibiting T cells in bone marrow. J Immunol 190:3815–3823. doi:10.4049/jimmunol.1203373

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  27. Rodriguez PC, Zea AH, Culotta KS et al (2002) Regulation of T cell receptor CD3zeta chain expression by l-arginine. J Biol Chem 277:21123–21129. doi:10.1074/jbc.M110675200

    Article  PubMed  CAS  Google Scholar 

  28. Whiteside TL (2004) Down-regulation of zeta-chain expression in T cells: a biomarker of prognosis in cancer? Cancer Immunol Immunother 53:865–878. doi:10.1007/s00262-004-0521-0

    PubMed  CAS  Google Scholar 

  29. Bronte V, Kasic T, Gri G et al (2005) Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers. J Exp Med 201:1257–1268. doi:10.1084/jem.20042028

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Meidenbauer N, Gooding W, Spitler L, Harris D, Whiteside TL (2002) Recovery of zeta-chain expression and changes in spontaneous IL-10 production after PSA-based vaccines in patients with prostate cancer. Br J Cancer 86(2):168–178

  31. Afonso G, Scotto M, Renand A et al (2010) Critical parameters in blood processing for T-cell assays: validation on ELISpot and tetramer platforms. J Immunol Methods 359:28–36. doi:10.1016/j.jim.2010.05.005

    Article  PubMed  CAS  Google Scholar 

  32. Derhovanessian E, Adams V, Hähnel K et al (2009) Pretreatment frequency of circulating IL-17+ CD4+ T-cells, but not Tregs, correlates with clinical response to whole-cell vaccination in prostate cancer patients. Int J Cancer 125:1372–1379. doi:10.1002/ijc.24497

    Article  PubMed  CAS  Google Scholar 

  33. Nishikawa H, Sakaguchi S (2010) Regulatory T cells in tumor immunity. Int J Cancer 127:759–767. doi:10.1002/ijc.25429

    PubMed  CAS  Google Scholar 

  34. Hoechst B, Ormandy LA, Ballmaier M 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. doi:10.1053/j.gastro.2008.03.020

    Article  PubMed  CAS  Google Scholar 

  35. Mougiakakos D, Choudhury A, Lladser A et al (2010) Regulatory T cells in cancer. Adv Cancer Res 107:57–117. doi:10.1016/S0065-230X(10)07003-X

    Article  PubMed  CAS  Google Scholar 

  36. Gregg R, Smith CM, Clark FJ et al (2005) The number of human peripheral blood CD4+ CD25high regulatory T cells increases with age. Clin Exp Immunol 140:540–546. doi:10.1111/j.1365-2249.2005.02798.x

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  37. Verschoor CP, Johnstone J, Millar J et al (2013) Blood CD33(+)HLA-DR(-) myeloid-derived suppressor cells are increased with age and a history of cancer. J Leukoc Biol 93:633–637. doi:10.1189/jlb.0912461

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Yuan X-K, Zhao X-K, Xia Y-C et al (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. doi:10.1177/147323001103900424

    Article  PubMed  CAS  Google Scholar 

  39. Diaz-Montero CM, Salem ML, Nishimura MI et al (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. doi:10.1007/s00262-008-0523-4

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  40. Arihara F, Mizukoshi E, Kitahara M 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. doi:10.1007/s00262-013-1447-1

    Article  PubMed  CAS  Google Scholar 

  41. Azevedo A, Cunha V, Teixeira AL, Medeiros R (2011) IL-6/IL-6R as a potential key signaling pathway in prostate cancer development. World J Clin Oncol 2:384–396. doi:10.5306/wjco.v2.i12.384

    Article  PubMed  PubMed Central  Google Scholar 

  42. Wu C-T, Hsieh C–C, Lin C–C et al (2012) Significance of IL-6 in the transition of hormone-resistant prostate cancer and the induction of myeloid-derived suppressor cells. J Mol Med 90:1343–1355. doi:10.1007/s00109-012-0916-x

    Article  PubMed  CAS  Google Scholar 

  43. Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061. doi:10.1126/science.1079490

    Article  PubMed  CAS  Google Scholar 

  44. Kleinewietfeld M, Starke M, Di Mitri D et al (2009) CD49d provides access to “untouched” human Foxp3+ Treg free of contaminating effector cells. Blood 113:827–836. doi:10.1182/blood-2008-04-150524

    Article  PubMed  CAS  Google Scholar 

  45. Weide B, Martens A, Zelba H 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. doi:10.1158/1078-0432.CCR-13-2508

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors thank Kirsten Nikolajsen for technical support and Tobias Wirenfeldt Klausen for assistance with the statistical analyses. Grants from the Danish Cancer Society, The Danielsen Foundation, and Toyota Fonden funded the study.

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None of the authors have any conflict of interest.

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Authors and Affiliations

  1. Department of Hematology, Center for Cancer Immune Therapy (CCIT), Copenhagen University Hospital Herlev, Herlev Ringvej 75, 2730, Herlev, Denmark

    Manja Idorn, Tania Køllgaard, Per Kongsted & Per thor Straten

  2. Department of Oncology, Copenhagen University Hospital , Herlev, Denmark

    Per Kongsted & Lisa Sengeløv

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  1. Manja Idorn
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  2. Tania Køllgaard
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  3. Per Kongsted
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Correspondence to Per thor Straten.

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Idorn, M., Køllgaard, T., Kongsted, P. et al. 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 (2014). https://doi.org/10.1007/s00262-014-1591-2

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  • DOI: https://doi.org/10.1007/s00262-014-1591-2

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