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

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.

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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.

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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.

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Authors

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.

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The authors declare no competing financial interests.

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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

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