[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
Skip to main content

Advertisement

Springer Nature Link
Log in

Circulating myeloid-derived suppressor cells increase in patients undergoing neo-adjuvant chemotherapy for breast cancer

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

This study sought to evaluate whether myeloid-derived suppressor cells (MDSC) could be affected by chemotherapy and correlate with pathologic complete response (pCR) in breast cancer patients receiving neo-adjuvant chemotherapy. Peripheral blood levels of granulocytic (G-MDSC) and monocytic (M-MDSC) MDSC were measured by flow cytometry prior to cycle 1 and 2 of doxorubicin and cyclophosphamide and 1st and last administration of paclitaxel or paclitaxel/anti-HER2 therapy. Of 24 patients, 11, 6 and 7 patients were triple negative, HER2+ and hormone receptor+, respectively. 45.8% had pCR. Mean M-MDSC% were <1. Mean G-MDSC% and 95% confidence intervals were 0.88 (0.23–1.54), 5.07 (2.45–7.69), 9.32 (4.02–14.61) and 1.97 (0.53–3.41) at draws 1–4. The increase in G-MDSC by draw 3 was significant (p < 0.0001) in all breast cancer types. G-MDSC levels at the last draw were numerically lower in patients with pCR (1.15; 95% CI 0.14–2.16) versus patients with no pCR (2.71; 95% CI 0–5.47). There was no significant rise in G-MDSC from draw 1 to 3 in African American patients, and at draw 3 G-MDSC levels were significantly lower in African Americans versus Caucasians (p < 0.05). It was concluded that G-MDSC% increased during doxorubicin and cyclophosphamide therapy, but did not significantly differ between patients based on pathologic complete response.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
£29.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (United Kingdom)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

CALGB:

Cancer and Leukemia Group B

G-CSF:

Granulocyte colony stimulating factor

G-MDSC:

Granulocytic MDSC

HR:

Hormone receptor

IRB:

Institutional review board

M-MDSC:

Monocytic MDSC

MDSC:

Myeloid-derived suppressor cell(s)

NAC:

Neo-adjuvant chemotherapy

PBMC:

Peripheral blood mononuclear cell(s)

pCR:

Pathologic complete response

RCB:

Residual cancer burden

TNBC:

Triple negative breast cancer

References

  1. Wesolowski R, Duggan M, Stiff A et al. (2016) Abstract P4-09-18: Characterization of circulating myeloid derived suppressor cells and cytokines in patients undergoing neo-adjuvant chemotherapy for breast cancer. Cancer Res 76(4):P4-09-18. doi:10.1158/1538-7445.SABCS15-P4-09-18 (Abstract P4-09-18)

    Article  Google Scholar 

  2. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  CAS  PubMed  Google Scholar 

  3. Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331:1565–1570. doi:10.1126/science.1203486

    Article  CAS  PubMed  Google Scholar 

  4. DeNardo DG, Brennan DJ, Rexhepaj E et al (2011) Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov 1:54–67. doi:10.1158/2159-8274.CD-10-0028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gajewski TF, Schreiber H, Fu Y-X (2013) Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 14:1014–1022. doi:10.1038/ni.2703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Markowitz J, Brooks TR, Duggan MC et al (2015) Patients with pancreatic adenocarcinoma exhibit elevated levels of myeloid-derived suppressor cells upon progression of disease. Cancer Immunol Immunother 64:149–159. doi:10.1007/s00262-014-1618-8

    Article  CAS  PubMed  Google Scholar 

  7. Wu X, Feng Q-M, Wang Y et al (2010) The immunologic aspects in advanced ovarian cancer patients treated with paclitaxel and carboplatin chemotherapy. Cancer Immunol Immunother 59:279–291. doi:10.1007/s00262-009-0749-9

    Article  CAS  PubMed  Google Scholar 

  8. Clynes RA, Towers TL, Presta LG, Ravetch JV (2000) Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med 6:443–446. doi:10.1038/74704

    Article  CAS  PubMed  Google Scholar 

  9. McDonnell AM, Nowak AK, Lake RA (2011) Contribution of the immune system to the chemotherapeutic response. Semin Immunopathol 33:353–367. doi:10.1007/s00281-011-0246-z

    Article  CAS  PubMed  Google Scholar 

  10. de Biasi AR, Villena-Vargas J, Adusumilli PS (2014) Cisplatin-induced antitumor immunomodulation: a review of preclinical and clinical evidence. Clin Cancer Res 20:5384–5391. doi:10.1158/1078-0432.CCR-14-1298

    Article  PubMed  PubMed Central  Google Scholar 

  11. Bronte V, Apolloni E, Cabrelle A et al (2000) Identification of a CD11b(+)/Gr-1(+)/CD31(+) myeloid progenitor capable of activating or suppressing CD8(+) T cells. Blood 96:3838–3846

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Corzo CA, Cotter MJ, Cheng P et al (2009) Mechanism regulating reactive oxygen species in tumor-induced myeloid-derived suppressor cells. J Immunol 182:5693–5701. doi:10.4049/jimmunol.0900092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Li H, Han Y, Guo Q et al (2009) Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-beta 1. J Immunol 182:240–249

    Article  CAS  PubMed  Google Scholar 

  14. 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  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bunt SK, Yang L, Sinha P et al (2007) Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression. Cancer Res 67:10019–10026. doi:10.1158/0008-5472.CAN-07-2354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Scholl SM, Pierga JY, Asselain B et al (1995) Breast tumour response to primary chemotherapy predicts local and distant control as well as survival. Eur J Cancer 31A:1969–1975

    Article  CAS  PubMed  Google Scholar 

  17. Rastogi P, Anderson SJ, Bear HD et al (2008) Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 26:778–785. doi:10.1200/JCO.2007.15.0235

    Article  PubMed  Google Scholar 

  18. Baselga J, Bradbury I, Eidtmann H et al (2012) Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet (London, England) 379:633–640. doi:10.1016/S0140-6736(11)61847-3

    Article  CAS  Google Scholar 

  19. Lesinski GB, Kondadasula SV, Crespin T et al (2004) Multiparametric flow cytometric analysis of inter-patient variation in STAT1 phosphorylation following interferon Alfa immunotherapy. J Natl Cancer Inst 96:1331–1342. doi:10.1093/jnci/djh252

    Article  CAS  PubMed  Google Scholar 

  20. Symmans WF, Peintinger F, Hatzis C et al (2007) Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 25:4414–4422. doi:10.1200/JCO.2007.10.6823

    Article  PubMed  Google Scholar 

  21. Mundy-Bosse BL, Young GS, Bauer T et al (2011) Distinct myeloid suppressor cell subsets correlate with plasma IL-6 and IL-10 and reduced interferon-alpha signaling in CD4+ T cells from patients with GI malignancy. Cancer Immunol Immunother 60:1269–1279. doi:10.1007/s00262-011-1029-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bronte V, Brandau S, Chen S-H et al (2016) Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 7:12150. doi:10.1038/ncomms12150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wesolowski R, Budd GT (2009) Neoadjuvant therapy for breast cancer: assessing treatment progress and managing poor responders. Curr Oncol Rep 11:37–44

    Article  CAS  PubMed  Google Scholar 

  24. Sikov WM, Berry DA, Perou CM et al (2015) Event-free and overall survival following neoadjuvant weekly paclitaxel and dose-dense AC ± carboplatin and/or bevacizumab in triple-negative breast cancer: outcomes from CALGB 40603 (Alliance). In: 2015 San Antonio Breast Cancer Symp. [Abstract]

  25. 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  CAS  PubMed  Google Scholar 

  26. Sinha P, Clements VK, Bunt SK et al (2007) Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J Immunol 179:977–983

    Article  CAS  PubMed  Google Scholar 

  27. Almand B, Resser JR, Lindman B et al (2000) Clinical significance of defective dendritic cell differentiation in cancer. Clin Cancer Res 6:1755–1766

    CAS  PubMed  Google Scholar 

  28. Cole S, Montero A, Garret-Mayer E et al (2009) Elevated circulating myeloid derived suppressor cells (MDSC) are associated with inferior overall survival (OS) and correlate with circulating tumor cells (CTC) in patients with metastatic breast cancer. Cancer Res 69:4135. doi:10.1158/0008-5472.SABCS-09-4135 [Abstract]

    Article  Google Scholar 

  29. Gabitass RF, Annels NE, Stocken DD et al (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 60:1419–1430. doi:10.1007/s00262-011-1028-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wesolowski R, Markowitz J, Carson WE (2013) Myeloid derived suppressor cells—a new therapeutic target in the treatment of cancer. J Immunother Cancer 1:10. doi:10.1186/2051-1426-1-10

    Article  PubMed  PubMed Central  Google Scholar 

  31. Mandruzzato S, Solito S, Falisi E et al (2009) IL4Ralpha+ myeloid-derived suppressor cell expansion in cancer patients. J Immunol 182:6562–6568. doi:10.4049/jimmunol.0803831

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work has been supported by the National Institutes of Health Grants 2P01CA095426-11, T32 GM068412 (to M. Duggan), K12 CA 133250 as well as the Ohio State Center for Clinical and Translational Science Richard P. and Marie R. Bremer Medical Research Fund and William H. Davis Endowment for Basic Medical Research Pilot Grant (UL1TR000090).

Author information

Author notes

  1. Robert Wesolowski and Megan C. Duggan contributed equally to this paper.

Authors and Affiliations

  1. Department of Internal Medicine, Division of Medical Oncology, The Ohio State University, Starling Loving Hall, 320 W10th Ave, Columbus, OH, 43210, USA

    Robert Wesolowski, Rachel Layman, Bhuvaneswari Ramaswamy, Erin R. Macrae, Maryam B. Lustberg, Raquel E. Reinbolt & Ewa Mrozek

  2. The Ohio State University Comprehensive Cancer Center, The Ohio State University, 410 W 12th Avenue, Columbus, OH, 43210, USA

    Megan C. Duggan, Andrew Stiff, Joseph Markowitz, Prashant Trikha, Kala M. Levine, John C. Byrd, Michael A. Caligiuri & Thomas A. Mace

  3. Department of Pathology, The Ohio State University, 410 W 10th Ave, N337B Doan Hall, Columbus, OH, 43210-1267, USA

    Lynn Schoenfield

  4. Center for Biostatistics, The Ohio State University, 2012 Kenny Rd, Columbus, OH, 43221, USA

    Mahmoud Abdel-Rasoul

  5. Division of Surgical Oncology, Department of Surgery, The Ohio State University, 410 W 10th Ave, N911 Doan Hall, Columbus, OH, 43210-1267, USA

    William E. Carson III

  6. Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, 33612, USA

    Joseph Markowitz

  7. Department of General Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Rachel Layman

Authors
  1. Robert Wesolowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Megan C. Duggan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrew Stiff
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Joseph Markowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Prashant Trikha
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kala M. Levine
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lynn Schoenfield
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mahmoud Abdel-Rasoul
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Rachel Layman
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bhuvaneswari Ramaswamy
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Erin R. Macrae
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Maryam B. Lustberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Raquel E. Reinbolt
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Ewa Mrozek
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. John C. Byrd
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Michael A. Caligiuri
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Thomas A. Mace
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. William E. Carson III
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to William E. Carson III.

Ethics declarations

Conflict of interest

The authors declare no commercial or financial conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 965 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wesolowski, R., Duggan, M.C., Stiff, A. et al. Circulating myeloid-derived suppressor cells increase in patients undergoing neo-adjuvant chemotherapy for breast cancer. Cancer Immunol Immunother 66, 1437–1447 (2017). https://doi.org/10.1007/s00262-017-2038-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-017-2038-3

Keywords

Search

Navigation