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.

  • Technical Report
  • Published:

Generation of a new therapeutic peptide that depletes myeloid-derived suppressor cells in tumor-bearing mice

Nature Medicine volume 20, pages 676–681 (2014)Cite this article

Subjects

Abstract

Immune evasion is an emerging hallmark of cancer progression. However, functional studies to understand the role of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment are limited by the lack of available specific cell surface markers. We adapted a competitive peptide phage display platform to identify candidate peptides binding MDSCs specifically and generated peptide-Fc fusion proteins (peptibodies). In multiple tumor models, intravenous peptibody injection completely depleted blood, splenic and intratumoral MDSCs in tumor-bearing mice without affecting proinflammatory immune cell types, such as dendritic cells. Whereas control Gr-1–specific antibody primarily depleted granulocytic MDSCs, peptibodies depleted both granulocytic and monocytic MDSC subsets. Peptibody treatment was associated with inhibition of tumor growth in vivo, which was superior to that achieved with Gr-1–specific antibody. Immunoprecipitation of MDSC membrane proteins identified S100 family proteins as candidate targets. Our strategy may be useful to identify new diagnostic and therapeutic surface targets on rare cell subtypes, including human MDSCs.

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

Figure 1: Identification and characterization of MDSC-binding peptides.
Figure 2: Generation and characterization of MDSC-specific peptibodies.
Figure 3: Peptibodies specifically depleted tumor-induced MDSCs in multiple tumor models and inhibited tumor growth in vivo.
Figure 4: Peptibodies recognize extracellular S100 family proteins on the surface of MDSCs.

Similar content being viewed by others

References

  1. Cheever, M.A. & Higano, C.S. PROVENGE (Sipuleucel-T) in prostate cancer: the first FDA-approved therapeutic cancer vaccine. Clin. Cancer Res. 17, 3520–3526 (2011).

    Article  Google Scholar 

  2. Schwartzentruber, D.J. et al. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N. Engl. J. Med. 364, 2119–2127 (2011).

    Article  CAS  Google Scholar 

  3. Schuster, S.J. et al. Vaccination with patient-specific tumor-derived antigen in first remission improves disease-free survival in follicular lymphoma. J. Clin. Oncol. 29, 2787–2794 (2011).

    Article  CAS  Google Scholar 

  4. Marigo, I., Dolcetti, L., Serafini, P., Zanovello, P. & Bronte, V. Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells. Immunol. Rev. 222, 162–179 (2008).

    Article  CAS  Google Scholar 

  5. Gabrilovich, D.I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9, 162–174 (2009).

    Article  CAS  Google Scholar 

  6. Peranzoni, E. et al. Myeloid-derived suppressor cell heterogeneity and subset definition. Curr. Opin. Immunol. 22, 238–244 (2010).

    Article  CAS  Google Scholar 

  7. Bronte, V. & Zanovello, P. Regulation of immune responses by l-arginine metabolism. Nat. Rev. Immunol. 5, 641–654 (2005).

    Article  CAS  Google Scholar 

  8. Rodriguez, P.C. et al. Regulation of T cell receptor CD3ζ chain expression by l-arginine. J. Biol. Chem. 277, 21123–21129 (2002).

    Article  CAS  Google Scholar 

  9. Ochoa, A.C., Zea, A.H., Hernandez, C. & Rodriguez, P.C. Arginase, prostaglandins, and myeloid-derived suppressor cells in renal cell carcinoma. Clin. Cancer Res. 13, 721s–726s (2007).

    Article  CAS  Google Scholar 

  10. Ugel, S. et al. Therapeutic targeting of myeloid-derived suppressor cells. Curr. Opin. Pharmacol. 9, 470–481 (2009).

    Article  CAS  Google Scholar 

  11. Vogl, T. et al. MRP8 and MRP14 control microtubule reorganization during transendothelial migration of phagocytes. Blood 104, 4260–4268 (2004).

    Article  CAS  Google Scholar 

  12. Cheng, P. et al. Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J. Exp. Med. 205, 2235–2249 (2008).

    Article  CAS  Google Scholar 

  13. Sinha, P. et al. Proinflammatory S100 proteins regulate the accumulation of myeloid-derived suppressor cells. J. Immunol. 181, 4666–4675 (2008).

    Article  CAS  Google Scholar 

  14. Ichikawa, M., Williams, R., Wang, L., Vogl, T. & Srikrishna, G. S100A8/A9 activate key genes and pathways in colon tumor progression. Mol. Cancer Res. 9, 133–148 (2011).

    Article  CAS  Google Scholar 

  15. Källberg, E. et al. S100A9 interaction with TLR4 promotes tumor growth. PLoS ONE 7, e34207 (2012).

    Article  Google Scholar 

  16. Zhao, F. et al. S100A9 a new marker for monocytic human myeloid-derived suppressor cells. Immunology 136, 176–183 (2012).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by a Developmental Research Program award to H.Q. from the US National Cancer Institute Specialized Programs of Research Excellence in Lymphoma (P50 CA136411). We thank D. Hawke for performing proteomic sequencing and analyzing results, D. Kusewitt (M.D. Anderson Cancer Center) for providing S100A9-deficient mice and D. Gwak for editing assistance.

Author information

Author notes

  1. Hong Qin, Beatrisa Lerman and Ippei Sakamaki: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Hong Qin, Beatrisa Lerman, Ippei Sakamaki, Guowei Wei, Soungchul C Cha, Sheetal S Rao, Jianfei Qian, Qing Yi & Larry W Kwak

  2. Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Hong Qin, Beatrisa Lerman, Ippei Sakamaki, Guowei Wei, Soungchul C Cha, Sheetal S Rao, Jianfei Qian, Yared Hailemichael, Roza Nurieva, Karen C Dwyer, Qing Yi, Willem W Overwijk & Larry W Kwak

  3. The University of Texas Graduate School of Biomedical Sciences, Houston, Texas, USA

    Beatrisa Lerman & Larry W Kwak

  4. Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Yared Hailemichael & Willem W Overwijk

  5. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Roza Nurieva

  6. Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Karen C Dwyer

  7. Institute of Immunology, University of Muenster, Muenster, Germany

    Johannes Roth

Authors
  1. Hong Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Beatrisa Lerman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ippei Sakamaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guowei Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Soungchul C Cha
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sheetal S Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jianfei Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yared Hailemichael
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Roza Nurieva
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Karen C Dwyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Johannes Roth
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Qing Yi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Willem W Overwijk
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Larry W Kwak
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

H.Q. designed the project and experiments, analyzed data and wrote the manuscript. B.L. and I.S. performed most of the experiments. G.W., S.S.R., S.C.C., J.Q., Y.H., R.N. and K.C.D. assisted with mouse studies, flow cytometry experiments and cell sorting. J.R., Q.Y. and W.W.O. provided S100A9-knockout mice, the EL4 tumor model and Gr-1–specific mAb, respectively, and also reviewed the manuscript. L.W.K. supervised the project, analyzed data and wrote the manuscript.

Corresponding author

Correspondence to Larry W Kwak.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6 and Supplementary Tables 1 and 2 (PDF 1837 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Qin, H., Lerman, B., Sakamaki, I. et al. Generation of a new therapeutic peptide that depletes myeloid-derived suppressor cells in tumor-bearing mice. Nat Med 20, 676–681 (2014). https://doi.org/10.1038/nm.3560

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3560

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing