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Cancer Immunology, Immunotherapy

, Volume 66, Issue 4, pp 503–513 | Cite as

Immunosuppressive myeloid-derived suppressor cells are increased in splenocytes from cancer patients

  • Kimberly R. Jordan
  • Puja Kapoor
  • Eric Spongberg
  • Richard P. Tobin
  • Dexiang Gao
  • Virginia F. Borges
  • Martin D. McCarter
Original Article

Abstract

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid cells that are increased in the peripheral blood of cancer patients and limit productive immune responses against tumors. Immunosuppressive MDSCs are well characterized in murine splenic tissue and are found at higher frequencies in spleens of tumor-bearing mice. However, no studies have yet analyzed these cells in parallel human spleens. We hypothesized that MDSCs would be increased in the spleens of human cancer patients, similar to tumor-bearing mice. We compared the frequency and function of MDSC subsets in dissociated human spleen from 16 patients with benign pancreatic cysts and 26 patients with a variety of cancers. We found that total MDSCs (Linneg CD11bpos CD33pos HLA-DRneg), granulocytic MDSCs (additional markers CD14neg CD15pos), and monocytic MDSCs (CD14pos CD15neg) were identified in human spleen. The monocytic subset was the most prominent in both spleen and peripheral blood and the granulocytic subset was expanded in the spleen relative to matched peripheral blood samples. Importantly, the frequency of CD15pos MDSCs in the spleen was increased in patients with cancer compared to patients with benign pancreatic cysts and was associated with a significantly increased risk of death and decreased overall survival. Finally, MDSCs isolated from the spleen suppressed T cell responses, demonstrating for the first time the functional capacity of human splenic MDSCs. These data suggest that the human spleen is a potential source of large quantities of cells with immunosuppressive function for future characterization and in-depth studies of human MDSCs.

Keywords

MDSCs Human spleen Immunosuppression Cancer 

Abbreviations

CFSE

Carboxyfluorescein succinimidyl ester

DMSO

Dimethyl sulfoxide

H&E

Hematoxylin and Eosin

MDSC

Myeloid-derived suppressor cell

MLR

Mixed-lymphocyte reaction

PBMC

Peripheral blood mononuclear cells

PBS

Phosphate-buffered saline

Notes

Acknowledgements

This work was supported by funding provided by the University of Colorado Cancer Center Support Grant (P30CA046934), American Cancer Society 2012 Roaring Fork Valley Postdoctoral Research Award, and the Conner Family Foundation Grant.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

262_2016_1953_MOESM1_ESM.pdf (572 kb)
Supplementary material 1 (PDF 571 KB)

References

  1. 1.
    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(18 Pt 1):5243–5248CrossRefPubMedGoogle Scholar
  2. 2.
    Mandruzzato S, Brandau S, Britten CM, Bronte V, Damuzzo V, Gouttefangeas C, Maurer D, Ottensmeier C, van der Burg SH, Welters MJ, Walter S (2016) Toward harmonized phenotyping of human myeloid-derived suppressor cells by flow cytometry: results from an interim study. Cancer Immunol Immunother 65(2):161–169CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Zea AH, Rodriguez PC, Atkins MB, Hernandez C, Signoretti S, Zabaleta J, McDermott D, Quiceno D, Youmans A, O’Neill A, Mier J, Ochoa AC (2005) Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res 65(8):3044–3048PubMedGoogle Scholar
  4. 4.
    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(1):234–243CrossRefPubMedGoogle Scholar
  5. 5.
    Bronte V, Brandau S, Chen SH, Colombo MP, Frey AB, Greten TF, Mandruzzato S, Murray PJ, Ochoa A, Ostrand-Rosenberg S, Rodriguez PC, Sica A, Umansky V, Vonderheide RH, Gabrilovich DI (2016) Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 7:12150CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Serafini P (2013) Myeloid derived suppressor cells in physiological and pathological conditions: the good, the bad, and the ugly. Immunol Res 57(1–3):172–184CrossRefPubMedGoogle Scholar
  7. 7.
    Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9(3):162–174CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Talmadge JE, Gabrilovich DI (2013) History of myeloid-derived suppressor cells. Nat Rev Cancer 13(10):739–752CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Solito S, Marigo I, Pinton L, Damuzzo V, Mandruzzato S, Bronte V (2014) Myeloid-derived suppressor cell heterogeneity in human cancers. Ann N Y Acad Sci 1319:47–65CrossRefPubMedGoogle Scholar
  10. 10.
    Jordan KR, Amaria RN, Ramirez O, Callihan EB, Gao D, Borakove M, Manthey E, Borges VF, McCarter MD (2013) Myeloid-derived suppressor cells are associated with disease progression and decreased overall survival in advanced-stage melanoma patients. Cancer Immunol Immunother 62(11):1711–1722CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    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):1419–1430CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Steiniger BS (2015) Human spleen microanatomy: why mice do not suffice. Immunology 145(3):334–346CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Zhao F, Obermann S, von Wasielewski R, Haile L, Manns MP, Korangy F, Greten TF (2009) Increase in frequency of myeloid-derived suppressor cells in mice with spontaneous pancreatic carcinoma. Immunology 128(1):141–149CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Clark CE, Hingorani SR, Mick R, Combs C, Tuveson DA, Vonderheide RH (2007) Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res 67(19):9518–9527CrossRefPubMedGoogle Scholar
  15. 15.
    Goedegebuure P, Mitchem JB, Porembka MR, Tan MC, Belt BA, Wang-Gillam A, Gillanders WE, Hawkins WG, Linehan DC (2011) Myeloid-derived suppressor cells: general characteristics and relevance to clinical management of pancreatic cancer. Curr Cancer Drug Targets 11(6):734–751CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Ghansah T, Vohra N, Kinney K, Weber A, Kodumudi K, Springett G, Sarnaik AA, Pilon-Thomas S (2013) Dendritic cell immunotherapy combined with gemcitabine chemotherapy enhances survival in a murine model of pancreatic carcinoma. Cancer Immunol Immunother 62(6):1083–1091CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Schmielau J, Finn OJ (2001) Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of t-cell function in advanced cancer patients. Cancer Res 61(12):4756–4760PubMedGoogle Scholar
  18. 18.
    Cress RD, Yin D, Clarke L, Bold R, Holly EA (2006) Survival among patients with adenocarcinoma of the pancreas: a population-based study (United States). Cancer Causes Control 17(4):403–409CrossRefPubMedGoogle Scholar
  19. 19.
    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(9):1373–1385CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    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):6713–6721CrossRefPubMedGoogle Scholar
  21. 21.
    Le HK, Graham L, Cha E, Morales JK, Manjili MH, Bear HD (2009) Gemcitabine directly inhibits myeloid derived suppressor cells in BALB/c mice bearing 4T1 mammary carcinoma and augments expansion of T cells from tumor-bearing mice. Int Immunopharmacol 9(7–8):900–909CrossRefPubMedGoogle Scholar
  22. 22.
    Bunt SK, Mohr AM, Bailey JM, Grandgenett PM, Hollingsworth MA (2013) Rosiglitazone and Gemcitabine in combination reduces immune suppression and modulates T cell populations in pancreatic cancer. Cancer Immunol Immunother 62(2):225–236CrossRefPubMedGoogle Scholar
  23. 23.
    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(1–2):14–22CrossRefPubMedPubMedCentralGoogle Scholar
  24. 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(4):1553–1560CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    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(19):5212–5223CrossRefPubMedGoogle Scholar
  26. 26.
    Younos I, Donkor M, Hoke T, Dafferner A, Samson H, Westphal S, Talmadge J (2011) Tumor- and organ-dependent infiltration by myeloid-derived suppressor cells. Int Immunopharmacol 11(7):816–826CrossRefPubMedGoogle Scholar
  27. 27.
    Youn JI, Nagaraj S, Collazo M, Gabrilovich DI (2008) Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J Immunol 181(8):5791–5802CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Freedman MH, Saunders EF (1981) Hematopoiesis in the human spleen. Am J Hematol 11(3):271–275CrossRefPubMedGoogle Scholar
  29. 29.
    Grizzle WE, Xu X, Zhang S, Stockard CR, Liu C, Yu S, Wang J, Mountz JD, Zhang HG (2007) Age-related increase of tumor susceptibility is associated with myeloid-derived suppressor cell mediated suppression of T cell cytotoxicity in recombinant inbred BXD12 mice. Mech Ageing Dev 128(11–12):672–680CrossRefPubMedGoogle Scholar
  30. 30.
    Bao Y, Mo J, Ruan L, Li G (2015) Increased monocytic CD14(+)HLADRlow/- myeloid-derived suppressor cells in obesity. Mol Med Rep 11(3):2322–8PubMedGoogle Scholar
  31. 31.
    Xia S, Sha H, Yang L, Ji Y, Ostrand-Rosenberg S, Qi L (2011) Gr-1 + CD11b + myeloid-derived suppressor cells suppress inflammation and promote insulin sensitivity in obesity. J Biol Chem 286(26):23591–23599CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Kasenda B, Bass A, Koeberle D, Pestalozzi B, Borner M, Herrmann R, Jost L, Lohri A, Hess V (2014) Survival in overweight patients with advanced pancreatic carcinoma: a multicentre cohort study. BMC Cancer 14:728CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Kusmartsev S, Gabrilovich DI (2003) Inhibition of myeloid cell differentiation in cancer: the role of reactive oxygen species. J Leukoc Biol 74(2):186–196CrossRefPubMedGoogle Scholar
  34. 34.
    Watanabe S, Deguchi K, Zheng R, Tamai H, Wang LX, Cohen PA, Shu S (2008) Tumor-induced CD11b + Gr-1 + myeloid cells suppress T cell sensitization in tumor-draining lymph nodes. J Immunol 181(5):3291–3300CrossRefPubMedGoogle Scholar
  35. 35.
    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):8270–8278CrossRefPubMedGoogle Scholar
  36. 36.
    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):6562–6568CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.Department of Surgery, School of MedicineUniversity of Colorado Denver Anschutz Medical CampusAuroraUSA
  2. 2.University of Colorado HospitalAuroraUSA
  3. 3.Department of Pediatrics, School of MedicineUniversity of Colorado Denver Anschutz Medical CampusAuroraUSA
  4. 4.Division of Medical Oncology, School of MedicineUniversity of Colorado Denver Anschutz Medical CampusAuroraUSA
  5. 5.Young Women’s Breast Cancer Translational ProgramUniversity of Colorado Denver Anschutz Medical CampusAuroraUSA
  6. 6.University of Colorado Cancer CenterAuroraUSA

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