Breast Cancer Research and Treatment

, Volume 123, Issue 1, pp 39–49

GM-CSF is one of the main breast tumor-derived soluble factors involved in the differentiation of CD11b-Gr1- bone marrow progenitor cells into myeloid-derived suppressor cells

  • Johanna K. Morales
  • Maciej Kmieciak
  • Keith L. Knutson
  • Harry D. Bear
  • Masoud H. Manjili
Preclinical study

Abstract

Recent reports have shown the involvement of tumor burden as well as GM-CSF in supporting myeloid-derived suppressor cells (MDSC). However, it is not known what progenitor cells may differentiate into MDSC in the presence of GM-CSF, and whether FVBN202 transgenic mouse model of spontaneous breast carcinoma may exhibit distinct subset distribution of CD11b+Gr1+ cells. In addition, it is not known why CD11b+Gr1+ cells derived from tumor-free and tumor-bearing animals exhibit different functions. In this study, we determined that GM-CSF was one of the tumor-derived soluble factors that induced differentiation of CD11b-Gr1- progenitor cells from within monocytic/granulocytic bone marrow cells into CD11b+Gr1+ cells. We also showed that CD11b+Gr1+ cells in FVBN202 mice consisted of CD11b+Ly6G-Ly6C+ suppressive and CD11b+Ly6G+Ly6C+ non-suppressive subsets. Previously reported variations between tumor-free and tumor-bearing animals in the function of their CD11b+Gr1+ cells were found to be due to the variations in the proportion of these two subsets. Therefore, increasing ratios of CD11b+Gr1+ cells derived from tumor-free animals revealed their suppressive activity on T cells, in vitro. Importantly, GM-CSF supported the generation of CD11b+Ly6G-Ly6C+ suppressor subsets that inhibited proliferation as well as anti-tumor function of neu-specific T cells. These findings suggest revisiting the use of GM-CSF for the expansion of dendritic cells, ex vivo, for cell-based immunotherapy or as an adjuvant for vaccines for patients with cancer in whom MDSC play a major role in the suppression of anti-tumor immune responses.

Keywords

Myeloid-derived suppressor cells (MDSC) GM-CSF Breast cancer Dendritic cells HER-2/neu 

Supplementary material

10549_2009_622_MOESM1_ESM.pdf (264 kb)
Supplementary material 1 (PDF 264 kb)

References

  1. 1.
    Gallina G, Dolcetti L, Serafini P et al (2006) Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells. J Clin Invest 116:2777–2790CrossRefPubMedGoogle Scholar
  2. 2.
    Youn JI, Nagaraj S, Collazo M, Gabrilovich DI (2008) Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J Immunol 181:5791–5802PubMedGoogle Scholar
  3. 3.
    Habibi M, Kmieciak M, Graham L, Morales JK, Bear HD, Manjili MH (2009) Radiofrequency thermal ablation of breast tumors combined with intralesional administration of IL-7 and IL-15 augments anti-tumor immune responses and inhibits tumor development and metastasis. Breast Cancer Res Treat 114:423–431CrossRefPubMedGoogle Scholar
  4. 4.
    Rodriguez PC, Hernandez CP, Quiceno D et al (2005) Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma. J Exp Med 202:931–939CrossRefPubMedGoogle Scholar
  5. 5.
    Ochoa AC, Zea AH, Hernandez C, Rodriguez PC (2007) Arginase, prostaglandins, and myeloid-derived suppressor cells in renal cell carcinoma. Clin Cancer Res 13:721s–726sCrossRefPubMedGoogle Scholar
  6. 6.
    Zea AH, Rodriguez PC, Atkins MB et al (2005) Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res 65:3044–3048PubMedGoogle Scholar
  7. 7.
    Valenti R, Huber V, Filipazzi P et al (2006) Human tumor-released microvesicles promote the differentiation of myeloid cells with transforming growth factor-beta-mediated suppressive activity on T lymphocytes. Cancer Res 66:9290–9298CrossRefPubMedGoogle Scholar
  8. 8.
    Young MR, Lathers DM (1999) Myeloid progenitor cells mediate immune suppression in patients with head and neck cancers. Int J Immunopharmacol 21:241–252CrossRefPubMedGoogle Scholar
  9. 9.
    Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ (2009) Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother 58:49–59CrossRefPubMedGoogle Scholar
  10. 10.
    Ezernitchi AV, Vaknin I, Cohen-Daniel L et al (2006) TCR zeta down-regulation under chronic inflammation is mediated by myeloid suppressor cells differentially distributed between various lymphatic organs. J Immunol 177:4763–4772PubMedGoogle Scholar
  11. 11.
    Gruber IV, El Yousfi S, Durr-Storzer S, Wallwiener D, Solomayer EF, Fehm T (2008) Down-regulation of CD28, TCR-zeta (zeta) and up-regulation of FAS in peripheral cytotoxic T-cells of primary breast cancer patients. Anticancer Res 28:779–784PubMedGoogle Scholar
  12. 12.
    Dworacki G, Meidenbauer N, Kuss I, Hoffmann TK, Gooding W, Lotze M, Whiteside TL (2001) Decreased zeta chain expression and apoptosis in CD3+ peripheral blood T lymphocytes of patients with melanoma. Clin Cancer Res 7:947s–957sPubMedGoogle Scholar
  13. 13.
    Takahashi A, Kono K, Amemiya H, Iizuka H, Fujii H, Matsumoto Y (2001) Elevated caspase-3 activity in peripheral blood T cells coexists with increased degree of T-cell apoptosis and down-regulation of TCR zeta molecules in patients with gastric cancer. Clin Cancer Res 7:74–80PubMedGoogle Scholar
  14. 14.
    Pan PY, Wang GX, Yin B et al (2008) Reversion of immune tolerance in advanced malignancy: modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function. Blood 111:219–228CrossRefPubMedGoogle Scholar
  15. 15.
    Melani C, Chiodoni C, Forni G, Colombo MP (2003) Myeloid cell expansion elicited by the progression of spontaneous mammary carcinomas in c-erbB-2 transgenic BALB/c mice suppresses immune reactivity. Blood 102:2138–2145CrossRefPubMedGoogle Scholar
  16. 16.
    Garrity T, Pandit R, Wright MA, Benefield J, Keni S, Young MR (1997) Increased presence of CD34+ cells in the peripheral blood of head and neck cancer patients and their differentiation into dendritic cells. Int J Cancer 73:663–669CrossRefPubMedGoogle Scholar
  17. 17.
    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 18:226–232CrossRefPubMedGoogle Scholar
  18. 18.
    Rosenberg SA, Yang JC, Schwartzentruber DJ et al (1999) Impact of cytokine administration on the generation of antitumor reactivity in patients with metastatic melanoma receiving a peptide vaccine. J Immunol 163:1690–1695PubMedGoogle Scholar
  19. 19.
    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 25:2546–2553CrossRefPubMedGoogle Scholar
  20. 20.
    Serafini P, Carbley R, Noonan KA, Tan G, Bronte V, Borrello I (2004) High-dose granulocyte-macrophage colony-stimulating factor-producing vaccines impair the immune response through the recruitment of myeloid suppressor cells. Cancer Res 64:6337–6343CrossRefPubMedGoogle Scholar
  21. 21.
    Rössner S, Voigtländer C, Wiethe C, Hänig J, Seifarth C, Lutz MB (2005) Myeloid dendritic cell precursors generated from bone marrow suppress T cell responses via cell contact and nitric oxide production in vitro. Eur J Immunol 35(12):3533–3544CrossRefPubMedGoogle Scholar
  22. 22.
    Movahedi K, Guilliams M, Van den Bossche J et al (2008) Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood 111:4233–4244CrossRefPubMedGoogle Scholar
  23. 23.
    Sawanobori Y, Ueha S, Kurachi M et al (2008) Chemokine-mediated rapid turnover of myeloid-derived suppressor cells in tumor-bearing mice. Blood 111:5457–5466CrossRefPubMedGoogle Scholar
  24. 24.
    Guy CT, Webster MA, Schaller M, Parsons TJ, Cardiff RD, Muller WJ (1992) Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc Natl Acad Sci USA 89:10578–10582CrossRefPubMedGoogle Scholar
  25. 25.
    Kmieciak M, Morales JK, Morales J, Bolesta E, Grimes M, Manjili MH (2008) Danger signals and nonself entity of tumor antigen are both required for eliciting effective immune responses against HER-2/neu positive mammary carcinoma: implications for vaccine design. Cancer Immunol Immunother 57:1391–1398CrossRefPubMedGoogle Scholar
  26. 26.
    Kmieciak M, Knutson KL, Dumur CI, Manjili MH (2007) HER-2/neu antigen loss and relapse of mammary carcinoma are actively induced by T cell-mediated anti-tumor immune responses. Eur J Immunol 37:675–685CrossRefPubMedGoogle Scholar
  27. 27.
    Morales JK, Kmieciak M, Graham L, Feldmesser M, Bear HD, Manjili MH (2009) Adoptive transfer of HER2/neu-specific T cells expanded with alternating gamma chain cytokines mediate tumor regression when combined with the depletion of myeloid-derived suppressor cells. Cancer Immunol Immunother 58(6):941–953CrossRefPubMedGoogle Scholar
  28. 28.
    Dugast AS, Haudebourg T, Coulon F et al (2008) Myeloid-derived suppressor cells accumulate in kidney allograft tolerance and specifically suppress effector T cell expansion. J Immunol 180(12):7898–7906PubMedGoogle Scholar
  29. 29.
    Marigo I, Dolcetti L, Serafini P, Zanovello P, Bronte V (2008) Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells. Immunol Rev 222:162–179CrossRefPubMedGoogle Scholar
  30. 30.
    Bronte V, Chappell DB, Apolloni E et al (1999) Unopposed production of granulocyte-macrophage colony-stimulating factor by tumors inhibits CD8+ T cell responses by dysregulating antigen-presenting cell maturation. J Immunol 162:5728–5737PubMedGoogle Scholar
  31. 31.
    Daud AI, Mirza N, Lenox B et al (2008) Phenotypic and functional analysis of dendritic cells and clinical outcome in patients with high-risk melanoma treated with adjuvant granulocyte macrophage colony-stimulating factor. J Clin Oncol 26:3235–3241CrossRefPubMedGoogle Scholar
  32. 32.
    Nefedova Y, Huang M, Kusmartsev S et al (2004) Hyperactivation of STAT3 is involved in abnormal differentiation of dendritic cells in cancer. J Immunol 172:464–474PubMedGoogle Scholar
  33. 33.
    Soria G, Ben-Baruch A (2008) The inflammatory chemokines CCL2 and CCL5 in breast cancer. Cancer Lett 267:271–285CrossRefPubMedGoogle Scholar
  34. 34.
    Yamashiro S, Takeya M, Nishi T et al (1994) Tumor-derived monocyte chemoattractant protein-1 induces intratumoral infiltration of monocyte-derived macrophage subpopulation in transplanted rat tumors. Am J Pathol 145:856–867PubMedGoogle Scholar
  35. 35.
    Rössner S, Voigtländer C, Wiethe C, Hänig J, Seifarth C, Lutz MB (2005) Myeloid dendritic cell precursors generated from bone marrow suppress T cell responses via cell contact and nitric oxide production in vitro. Eur J Immunol 35:3533–3544CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Johanna K. Morales
    • 1
  • Maciej Kmieciak
    • 1
  • Keith L. Knutson
    • 2
  • Harry D. Bear
    • 3
  • Masoud H. Manjili
    • 1
  1. 1.Department of Microbiology & ImmunologyVirginia Commonwealth University School of Medicine, Massey Cancer CenterRichmondUSA
  2. 2.Department of ImmunologyMayo Clinic College of MedicineRochesterUSA
  3. 3.Department of SurgeryVirginia Commonwealth University School of Medicine, Massey Cancer CenterRichmondUSA

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