Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

The transcriptional profile of circulating myeloid derived suppressor cells correlates with tumor development and progression in mouse

Genes & Immunity volume 20, pages 589–598 (2019)Cite this article

Subjects

Abstract

Myeloid derived suppressor cells (MDSCs) play key roles in cancer development. Accumulation of peripheral-blood MDSCs (PB-MDSCs) corresponds to the progression of various cancers, but provides only a crude indicator. We aimed toward identifying changes in the transcriptional profile of PB-MDSCs in response to tumor growth. CT26 colon cancer cells and B16 melanoma cells (106) were inoculated into peritoneal cavities of BALB/c mice and subcutaneously to C57-black mice, respectively. The circulating levels and global transcriptional patterns of PB CD11b+Ly6g+ MDSCs were assessed in control mice, and 4, 8, and 11 days following tumor cell inoculation. Although a significant accumulation of PB-MDSCs was demonstrated only 11 days following tumor induction, a pronounced transcriptional response was identified already on day 4 while the tumor was ~1 mm in size. Further transcriptional changes correlated with different stages of tumor growth. Key MDSC genes and canonical signaling pathways were activated along tumor progression. This phenomenon was demonstrated in both cancer models, and a consensus set of 817 genes, involved in myeloid cell recruitment and angiogenesis, was identified. The data suggest that the transcriptional signatures of PB-MDSC may serve as markers for tumor progression, as well as providing potential targets for future therapies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Folkman J, Kalluri R. Cancer without disease. Nature. 2004;427:787.

    Article  CAS  PubMed  Google Scholar 

  2. Gimbrone MA, Jr, Leapman SB, Cotran RS, Folkman J. Tumor dormancy in vivo by prevention of neovascularization. J Exp Med. 1972;136:261–76.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Folkman J, Klagsbrun M. Angiogenic factors. Science. 1987;235:442–7.

    Article  CAS  PubMed  Google Scholar 

  4. Yang L, DeBusk LM, Fukuda K, Fingleton B, Green-Jarvis B, Shyr Y, et al. Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell. 2004;6:409–21.

    Article  CAS  PubMed  Google Scholar 

  5. Sica A, Porta C, Amadori A, Pasto A. Tumor-associated myeloid cells as guiding forces of cancer cell stemness. Cancer Immunol Immunother. 2017;66:1025–36.

    Article  CAS  PubMed  Google Scholar 

  6. Yan HH, Pickup M, Pang Y, Gorska AE, Li Z, Chytil A, et al. Gr-1+CD11b+ myeloid cells tip the balance of immune protection to tumor promotion in the premetastatic lung. Cancer Res. 2010;70:6139–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Okazaki T, Ebihara S, Asada M, Kanda A, Sasaki H, Yamaya M. Granulocyte colony-stimulating factor promotes tumor angiogenesis via increasing circulating endothelial progenitor cells and Gr1+CD11b+ cells in cancer animal models. Int Immunol. 2006;18:1–9.

    Article  CAS  PubMed  Google Scholar 

  8. Shojaei F, Ferrara N. Refractoriness to antivascular endothelial growth factor treatment: role of myeloid cells. Cancer Res. 2008;68:5501–4.

    Article  CAS  PubMed  Google Scholar 

  9. Shojaei F, Wu X, Malik AK, Zhong C, Baldwin ME, Schanz S, et al. Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nat Biotechnol. 2007;25:911–20.

    Article  CAS  PubMed  Google Scholar 

  10. Zhao L, Lim SY, Gordon-Weeks AN, Tapmeier TT, Im JH, Cao Y, et al. Recruitment of a myeloid cell subset (CD11b/Gr1 mid) via CCL2/CCR2 promotes the development of colorectal cancer liver metastasis. Hepatology. 2013;57:829–39.

    Article  CAS  PubMed  Google Scholar 

  11. Panni RZ, Sanford DE, Belt BA, Mitchem JB, Worley LA, Goetz BD, et al. Tumor-induced STAT3 activation in monocytic myeloid-derived suppressor cells enhances stemness and mesenchymal properties in human pancreatic cancer. Cancer Immunol Immunother. 2014;63:513–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ichikawa M, Williams R, Wang L, Vogl T, Srikrishna G. S100A8/A9 activate key genes and pathways in colon tumor progression. Mol Cancer Res. 2011;9:133–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Diaz-Montero CM, Finke J, Montero AJ. Myeloid-derived suppressor cells in cancer: therapeutic, predictive, and prognostic implications. Semin Oncol. 2014;41:174–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gabrilovich DI. Myeloid-derived suppressor cells. Cancer Immunol Res. 2017;5:3–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kumar V, Patel S, Tcyganov E, Gabrilovich DI. The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol. 2016;37:208–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gabitass RF, Annels NE, Stocken DD, Pandha HA, Middleton GW. 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. 2011;60:1419–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sun HL, Zhou X, Xue YF, Wang K, Shen YF, Mao JJ, et al. Increased frequency and clinical significance of myeloid-derived suppressor cells in human colorectal carcinoma. World J Gastroenterol. 2012;18:3303–9.

    PubMed  PubMed Central  Google Scholar 

  18. Khaled YS, Ammori BJ, Elkord E. Increased levels of granulocytic myeloid-derived suppressor cells in peripheral blood and tumour tissue of pancreatic cancer patients. J Immunol Res. 2014;2014:879897.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Zhang B, Wang Z, Wu L, Zhang M, Li W, Ding J, et al. Circulating and tumor-infiltrating myeloid-derived suppressor cells in patients with colorectal carcinoma. PLoS ONE. 2013;8:e57114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Choi J, Maeng HG, Lee SJ, Kim YJ, Kim DW, Lee HN, et al. Diagnostic value of peripheral blood immune profiling in colorectal cancer. Ann Surg Treat Res. 2018;94:312–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Jin G, Zhang Y, Chang X, Zhang Y, Xu J, Wei M, et al. Increased percentage of mo-MDSCs in human peripheral blood may be a potential indicator in the diagnosis of breast cancer. Oncol Res Treat. 2017;40:603–8.

    Article  CAS  PubMed  Google Scholar 

  22. Toor SM, Syed Khaja AS, El Salhat H, Bekdache O, Kanbar J, Jaloudi M, et al. Increased levels of circulating and tumor-infiltrating granulocytic myeloid cells in colorectal cancer patients. Front Immunol. 2016;7:560.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Weide B, Martens A, Zelba H, Stutz C, Derhovanessian E, Di Giacomo AM, et al. 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. 2014;20:1601–9.

    Article  CAS  PubMed  Google Scholar 

  24. Huang H, Zhang G, Li G, Ma H, Zhang X. Circulating CD14(+)HLA-DR(−/low) myeloid-derived suppressor cell is an indicator of poor prognosis in patients with ESCC. Tumour Biol. 2015;36:7987–96.

    Article  CAS  PubMed  Google Scholar 

  25. Angell TE, Lechner MG, Smith AM, Martin SE, Groshen SG, Maceri DR, et al. Circulating myeloid-derived suppressor cells predict differentiated thyroid cancer diagnosis and extent. Thyroid. 2016;26:381–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tian T, Gu X, Zhang B, Liu Y, Yuan C, Shao L, et al. Increased circulating CD14(+)HLA-DR−/low myeloid-derived suppressor cells are associated with poor prognosis in patients with small-cell lung cancer. Cancer Biomark: Sect A Dis Markers. 2015;15:425–32.

    Article  Google Scholar 

  27. Yang G, Shen W, Zhang Y, Liu M, Zhang L, Liu Q, et al. Accumulation of myeloid-derived suppressor cells (MDSCs) induced by low levels of IL-6 correlates with poor prognosis in bladder cancer. Oncotarget. 2017;8:38378–88.

    PubMed  PubMed Central  Google Scholar 

  28. Soler DC, Young AB, Cooper KD, Kerstetter-Fogle A, Barnholtz-Sloan JS, Gittleman H, et al. The ratio of HLA-DR and VNN2(+) expression on CD14(+) myeloid derived suppressor cells can distinguish glioblastoma from radiation necrosis patients. J Neurooncol. 2017;134:189–96.

    Article  CAS  PubMed  Google Scholar 

  29. Veglia F, Perego M, Gabrilovich D. Myeloid-derived suppressor cells coming of age. Nat Immunol. 2018;19:108–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pencovich N, Hantisteanu S, Wurtzel O, Hallak M, Fainaru O. Unique expression patterns associated with preferential recruitment of immature myeloid cells into angiogenic versus dormant tumors. Genes Immun. 2013;14:90–8.

    Article  CAS  PubMed  Google Scholar 

  31. Fainaru O, Pencovich N, Hantisteanu S, Yona G, Hallak M. Immature myeloid cells derived from mouse placentas and malignant tumors demonstrate similar proangiogenic transcriptional signatures. Fertil Steril. 2013;99:910–7 e2.

    Article  CAS  PubMed  Google Scholar 

  32. Nueda MJ, Tarazona S, Conesa A. Next maSigPro: updating maSigPro bioconductor package for RNA-seq time series. Bioinformatics. 2014;30:2598–602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang D, An G, Xie S, Yao Y, Feng G. The clinical and prognostic significance of CD14(+)HLA-DR(−/low) myeloid-derived suppressor cells in hepatocellular carcinoma patients receiving radiotherapy. Tumour Biol. 2016;37:10427–33.

    Article  CAS  PubMed  Google Scholar 

  34. Arihara F, Mizukoshi E, Kitahara M, Takata Y, Arai K, Yamashita T, et al. Increase in CD14+HLA-DR−/low myeloid-derived suppressor cells in hepatocellular carcinoma patients and its impact on prognosis. Cancer Immunol Immunother. 2013;62:1421–30.

    Article  CAS  PubMed  Google Scholar 

  35. Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother. 2009;58:49–59.

    Article  CAS  PubMed  Google Scholar 

  36. Jordan KR, Amaria RN, Ramirez O, Callihan EB, Gao D, Borakove M, et al. Myeloid-derived suppressor cells are associated with disease progression and decreased overall survival in advanced-stage melanoma patients. Cancer Immunol Immunother. 2013;62:1711–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zaslavsky A, Chen C, Grillo J, Baek KH, Holmgren L, Yoon SS, et al. Regional control of tumor growth. Mol Cancer Res. 2010;8:1198–206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9:162–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Giallongo C, Tibullo D, Parrinello NL, La Cava P, Di Rosa M, Bramanti V, et al. Granulocyte-like myeloid derived suppressor cells (G-MDSC) are increased in multiple myeloma and are driven by dysfunctional mesenchymal stem cells (MSC). Oncotarget. 2016;7:85764–75.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Hawila E, Razon H, Wildbaum G, Blattner C, Sapir Y, Shaked Y, et al. CCR5 directs the mobilization of CD11b(+)Gr1(+)Ly6C(low) polymorphonuclear myeloid cells from the bone marrow to the blood to support tumor development. Cell Rep. 2017;21:2212–22.

    Article  CAS  PubMed  Google Scholar 

  41. Pio R, Ajona D, Lambris JD. Complement inhibition in cancer therapy. Semin Immunol. 2013;25:54–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg SL. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 2013;14:R36.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Anders S, Pyl PT, Huber W. HTSeq—a Python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31:166–9.

    Article  CAS  PubMed  Google Scholar 

  44. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Anders S, McCarthy DJ, Chen Y, Okoniewski M, Smyth GK, Huber W, et al. Count-based differential expression analysis of RNA sequencing data using R and Bioconductor. Nat Protoc. 2013;8:1765–86.

    Article  PubMed  Google Scholar 

  46. Edgar R, Domrachev M, Lash AE. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 2002;30:207–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

GF is the incumbent of the David and Stacey Cynamon Research fellow Chair in genetics and personalized medicine.

Author information

Author notes

  1. These authors contributed equally: Ido Nachmany, Yoel Bogoch

Authors and Affiliations

  1. The Laboratory of Molecular Genetics, HPB Cancer Research, Department of Surgery B, the Surgical Division, Tel-Aviv Sourasky Medical Center, The Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

    Ido Nachmany, Yoel Bogoch, Omer Amar, Ekaterina Bondar, Nitzan Zohar, Nir Lubezky, Joseph M. Klausner & Niv Pencovich

  2. Ilana and Pascal Mantoux Institute for Bioinformatics, Nancy and Stephen Grand Israel National Center for Personalized Medicine, The Weizmann Institute of Science, Rehovot, Israel

    Gilgi Friedlander-Malik

  3. Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel

    Shay Hantisteanu

  4. IVF Unit, Department of Obstetrics and Gynecology, Rambam Medical Center, Haifa, Israel

    Ofer Fainaru

Authors
  1. Ido Nachmany
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yoel Bogoch
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gilgi Friedlander-Malik
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Omer Amar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ekaterina Bondar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nitzan Zohar
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shay Hantisteanu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ofer Fainaru
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Nir Lubezky
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Joseph M. Klausner
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Niv Pencovich
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Niv Pencovich.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nachmany, I., Bogoch, Y., Friedlander-Malik, G. et al. The transcriptional profile of circulating myeloid derived suppressor cells correlates with tumor development and progression in mouse. Genes Immun 20, 589–598 (2019). https://doi.org/10.1038/s41435-019-0062-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41435-019-0062-3

This article is cited by

Search

Advanced search

Quick links