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Journal of Cancer Research and Clinical Oncology

, Volume 145, Issue 2, pp 329–336 | Cite as

Decitabine shows potent anti-myeloma activity by depleting monocytic myeloid-derived suppressor cells in the myeloma microenvironment

  • Jihao Zhou
  • Qi Shen
  • Haiqing Lin
  • Lina Hu
  • Guoqiang Li
  • Xinyou ZhangEmail author
Original Article – Cancer Research

Abstract

Purpose

Multiple myeloma (MM) remains incurable. The MM microenvironment supports MM cells’ survival and immune escape. Because myeloid-derived suppressor cells (MDSCs) is important in the MM microenvironment, and demethylating agent decitabine (DAC) can deplete MDSCs in vitro and in vivo, we hypothesized that DAC treatment could inhibit MM by depleting MDSCs in the MM microenvironment.

Methods

In this study, we used the mouse IL6 secreting, myeloma cell line MPC11 as a model. MDSCs were sorted using magnetic beads and cultured. A transwell coculture assay was used to mimic the microenvironment in vitro. And MPC11-bearing mice model was used to observe the efficacy of DAC treatment in vivo.

Results

In vitro coculture assay indicated that MPC11 cells showed significantly lower proliferation rate, less IL6 production and more apoptosis when they were cocultured with bone marrow cells without MDSCs (nonMDSCs) or DAC-treated bone marrow cells (DAC BMs) than with MDSCs or PBS-treated bone marrow cells (CTR BM). Supplementation with M-MDSCs rescued the inhibitory effect of DAC BMs, while additional NOHA supplementation further antagonized the rescue effect of M-MDSCs. In MPC11-bearing mice, the combined treatment of DAC with anti-Gr1 antibody showed synergistic effect on inhibiting tumor growth and promoting T cell infiltration in the tumor tissue. M-MDSC reinfusion also antagonized the efficacy of DAC treatment.

Conclusions

DAC treatment can inhibit myeloma cell proliferation and induce enhanced autologous T cell immune response by depleting M-MDSCs in the MM microenvironment. We believe that DAC treatment could improve the prognosis of MM in future.

Keywords

Decitabine Myeloid-derived suppressor cells Myeloma Microenvironment 

Abbreviations

MM

Multiple myeloma

MDSC

Myeloid-derived suppressor cells

M-MDSC

Monocytic myeloid-derived suppressor cells

G-MDSC

Granulocytic myeloid-derived suppressor cells

IL6

Interleukin 6

DAC

Decitabine

CTR

Control

BM

Bone marrow

nonMDSC

Bone marrow cells without MDSC

Tc cells

Cytotoxic T cells

Th cells

Helper T cells

Notes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81600168 and 81702082), the Basic Research Project of Shenzhen Science and Technology Program (No. JCYJ20160422145031770), and the Sanming Project of Medicine in Shenzhen (No. SZSM201512006). We thank Yushi Yao from McMaster Immunology Research Centre, McMaster University (Hamilton, Ontario, Canada) for the helpful discussion and technical support.

Funding

This work was supported by the National Natural Science Foundation of China (Nos. 81600168 and 81702082), the Basic Research Project of Shenzhen Science and Technology Program (No. JCYJ20160422145031770), and the Sanming Project of Medicine in Shenzhen (No. SZSM201512006).

Compliance with ethical standards

Conflict of interest

Author Jihao Zhou declares that he has no conflict of interest. Author Qi Shen declares that he has no conflict of interest. Author Haiqing Lin declares that he has no conflict of interest. Author Lina Hu declares that he has no conflict of interest. Author Guoqiang Li declares that he has no conflict of interest. Author Xinyou Zhang declares that he has no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.

References

  1. Amin SB et al (2014) Gene expression profile alone is inadequate in predicting complete response in multiple myeloma. Leukemia 28:2229–2234.  https://doi.org/10.1038/leu.2014.140 CrossRefGoogle Scholar
  2. Belyaev NN, Abdolla N, Perfilyeva YV, Ostapchuk YO, Krasnoshtanov VK, Kali A, Tleulieva R (2018) Daunorubicin conjugated with alpha-fetoprotein selectively eliminates myeloid-derived suppressor cells (MDSCs) and inhibits experimental tumor growth. Cancer Immunol Immunother CII 67:101–111.  https://doi.org/10.1007/s00262-017-2067-y CrossRefGoogle Scholar
  3. Bianchi G, Munshi NC (2015) Pathogenesis beyond the cancer clone(s) in multiple myeloma. Blood 125:3049–3058.  https://doi.org/10.1182/blood-2014-11-568881 CrossRefGoogle Scholar
  4. Binsfeld M et al (2016) Granulocytic myeloid-derived suppressor cells promote angiogenesis in the context of multiple myeloma. Oncotarget 7:37931–37943.  https://doi.org/10.18632/oncotarget.9270 CrossRefGoogle Scholar
  5. Botta C, Gulla A, Correale P, Tagliaferri P, Tassone P (2014) Myeloid-derived suppressor cells in multiple myeloma: pre-clinical research and translational opportunities. Front Oncol 4:348.  https://doi.org/10.3389/fonc.2014.00348 CrossRefGoogle Scholar
  6. Chim CS et al (2018) Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond. Leukemia 32:252–262.  https://doi.org/10.1038/leu.2017.329 CrossRefGoogle Scholar
  7. de Coana YP et al (2017) Ipilimumab treatment decreases monocytic MDSCs and increases CD8 effector memory T cells in long-term survivors with advanced melanoma. Oncotarget 8:21539–21553.  https://doi.org/10.18632/oncotarget.15368 CrossRefGoogle Scholar
  8. Domenis R et al (2017) Systemic T cells immunosuppression of glioma stem cell-derived exosomes is mediated by monocytic myeloid-derived suppressor cells. PLoS One 12:e0169932.  https://doi.org/10.1371/journal.pone.0169932 CrossRefGoogle Scholar
  9. Du J, Sun X, Song Y (2017) The study of CD14+ HLA-DR-/low myeloid-drived suppressor cell (MDSC) in peripheral blood of peripheral T-cell lymphoma patients and its biological function. Cell Mol Biol (Noisy-le-Grand, France) 63:62–67.  https://doi.org/10.14715/cmb/2017.63.3.12 CrossRefGoogle Scholar
  10. Giallongo C et al (2016) Granulocyte-like myeloid derived suppressor cells (G-MDSC) are increased in multiple myeloma and are driven by dysfunctional mesenchymal stem cells (MSC). Oncotarget 7:85764–85775.  https://doi.org/10.18632/oncotarget.7969 CrossRefGoogle Scholar
  11. Giallongo C et al (2018) Monocytic myeloid-derived suppressor cells as prognostic factor in chronic myeloid leukaemia patients treated with dasatinib. J Cell Mol Med 22:1070–1080.  https://doi.org/10.1111/jcmm.13326 Google Scholar
  12. Gorgun GT et al (2013) Tumor-promoting immune-suppressive myeloid-derived suppressor cells in the multiple myeloma microenvironment in humans. Blood 121:2975–2987.  https://doi.org/10.1182/blood-2012-08-448548 CrossRefGoogle Scholar
  13. Iclozan C, Antonia S, Chiappori A, Chen DT, Gabrilovich D (2013) Therapeutic regulation of myeloid-derived suppressor cells and immune response to cancer vaccine in patients with extensive stage small cell lung cancer. Cancer Immunol Immunother CII 62:909–918.  https://doi.org/10.1007/s00262-013-1396-8 CrossRefGoogle Scholar
  14. Kittang AO et al (2016) Expansion of myeloid derived suppressor cells correlates with number of T regulatory cells and disease progression in myelodysplastic syndrome. Oncoimmunology 5:e1062208.  https://doi.org/10.1080/2162402x.2015.1062208 CrossRefGoogle Scholar
  15. Lee SE et al (2016) Circulating immune cell phenotype can predict the outcome of lenalidomide plus low-dose dexamethasone treatment in patients with refractory/relapsed multiple myeloma. Cancer Immunol Immunother CII 65:983–994.  https://doi.org/10.1007/s00262-016-1861-2 CrossRefGoogle Scholar
  16. Mikyskova R et al (2014) DNA demethylating agent 5-azacytidine inhibits myeloid-derived suppressor cells induced by tumor growth and cyclophosphamide treatment. J Leukoc Biol 95:743–753.  https://doi.org/10.1189/jlb.0813435 CrossRefGoogle Scholar
  17. Ornstein MC et al (2018) Myeloid-derived suppressors cells (MDSC) correlate with clinicopathologic factors and pathologic complete response (pCR) in patients with urothelial carcinoma (UC) undergoing cystectomy. Urol Oncol.  https://doi.org/10.1016/j.urolonc.2018.02.018 Google Scholar
  18. Pogoda K, Pyszniak M, Rybojad P, Tabarkiewicz J (2016) Monocytic myeloid-derived suppressor cells as a potent suppressor of tumor immunity in non-small cell lung cancer. Oncol Lett 12:4785–4794.  https://doi.org/10.3892/ol.2016.5273 CrossRefGoogle Scholar
  19. Ramachandran IR et al (2013) Myeloid-derived suppressor cells regulate growth of multiple myeloma by inhibiting T cells in bone marrow. J Immunol (Baltimore, Md: 1950) 190:3815–3823.  https://doi.org/10.4049/jimmunol.1203373 CrossRefGoogle Scholar
  20. Saleh MH, Wang L, Goldberg MS (2016) Improving cancer immunotherapy with DNA methyltransferase inhibitors. Cancer Immunol Immunother CII 65:787–796.  https://doi.org/10.1007/s00262-015-1776-3 CrossRefGoogle Scholar
  21. Sasso MS et al (2016) Low dose gemcitabine-loaded lipid nanocapsules target monocytic myeloid-derived suppressor cells and potentiate cancer immunotherapy. Biomaterials 96:47–62.  https://doi.org/10.1016/j.biomaterials.2016.04.010 CrossRefGoogle Scholar
  22. Serafini P et al (2006) Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med 203:2691–2702.  https://doi.org/10.1084/jem.20061104 CrossRefGoogle Scholar
  23. Speigl L, Burow H, Bailur JK, Janssen N, Walter CB, Pawelec G, Shipp C (2018) CD14 + HLA-DR-/low MDSCs are elevated in the periphery of early-stage breast cancer patients and suppress autologous T cell proliferation. Breast Cancer Res Treat 168:401–411.  https://doi.org/10.1007/s10549-017-4594-9 CrossRefGoogle Scholar
  24. Stone ML et al (2017) Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden. Proc Natl Acad Sci USA 114:E10981–E10990.  https://doi.org/10.1073/pnas.1712514114 CrossRefGoogle Scholar
  25. Terracina KP, Graham LJ, Payne KK, Manjili MH, Baek A, Damle SR, Bear HD (2016) DNA methyltransferase inhibition increases efficacy of adoptive cellular immunotherapy of murine breast cancer. Cancer Immunol Immunother CII 65:1061–1073.  https://doi.org/10.1007/s00262-016-1868-8 CrossRefGoogle Scholar
  26. Van Valckenborgh E et al (2012) Multiple myeloma induces the immunosuppressive capacity of distinct myeloid-derived suppressor cell subpopulations in the bone marrow. Leukemia 26:2424–2428.  https://doi.org/10.1038/leu.2012.113 CrossRefGoogle Scholar
  27. Veltman JD, Lambers ME, van Nimwegen M, Hendriks RW, Hoogsteden HC, Aerts JG, Hegmans JP (2010) COX-2 inhibition improves immunotherapy and is associated with decreased numbers of myeloid-derived suppressor cells in mesothelioma. Celecoxib influences MDSC function. BMC Cancer 10:464.  https://doi.org/10.1186/1471-2407-10-464 CrossRefGoogle Scholar
  28. Wang J et al (2015a) The bone marrow microenvironment enhances multiple myeloma progression by exosome-mediated activation of myeloid-derived suppressor cells. Oncotarget 6:43992–44004.  https://doi.org/10.18632/oncotarget.6083 Google Scholar
  29. Wang Z et al (2015b) Tumor-induced CD14+ HLA-DR (-/low) myeloid-derived suppressor cells correlate with tumor progression and outcome of therapy in multiple myeloma patients. Cancer Immunol Immunother CII 64:389–399.  https://doi.org/10.1007/s00262-014-1646-4 CrossRefGoogle Scholar
  30. Wang J, De Veirman K, Faict S, Frassanito MA, Ribatti D, Vacca A, Menu E (2016) Multiple myeloma exosomes establish a favourable bone marrow microenvironment with enhanced angiogenesis and immunosuppression. J Pathol 239:162–173.  https://doi.org/10.1002/path.4712 CrossRefGoogle Scholar
  31. Wu C et al (2015) Prognostic significance of peripheral monocytic myeloid-derived suppressor cells and monocytes in patients newly diagnosed with diffuse large b-cell lymphoma. Int J Clin Exp Med 8:15173–15181Google Scholar
  32. Youn JI et al (2013) Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer. Nat Immunol 14:211–220.  https://doi.org/10.1038/ni.2526 CrossRefGoogle Scholar
  33. Zhou JH et al (2013) Demethylating agent decitabine induces autologous cancer testis antigen specific cytotoxic T lymphocytes in vivo. Chin Med J 126:4552–4556Google Scholar
  34. Zhou J, Yao Y, Shen Q, Li G, Hu L, Zhang X (2017) Demethylating agent decitabine disrupts tumor-induced immune tolerance by depleting myeloid-derived suppressor cells. J Cancer Res Clin Oncol 143:1371–1380.  https://doi.org/10.1007/s00432-017-2394-6 CrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  1. 1.Department of Hematology, The Second Clinical Medical College (Shenzhen People’s Hospital)Jinan UniversityShenzhenPeople’s Republic of China

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