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

• Published in: Nature medicine Vol. 20; no. 6; pp. 676 - 681
• Main Authors: Qin, Hong, Lerman, Beatrisa, Sakamaki, Ippei, Wei, Guowei, Cha, Soungchul C, Rao, Sheetal S, Qian, Jianfei, Hailemichael, Yared, Nurieva, Roza, Dwyer, Karen C, Roth, Johannes, Yi, Qing, Overwijk, Willem W, Kwak, Larry W
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-06-2014; Nature Publishing Group
• Subjects: 13/31; 38/109; 631/1647/664/2228; 64/60; 82/1; 82/80; 82/81; 82/83; Analysis; Animals; Biomedicine; Blood; Cancer Research; Care and treatment; Development and progression; Genetic aspects; Health aspects; Immune response; Immunoglobulins; Immunoprecipitation; Immunotherapy; Infectious Diseases; Injection; Metabolic Diseases; Mice; Molecular Medicine; Myeloid Cells - drug effects; Myeloid Cells - immunology; Neoplasms - drug therapy; Neoplasms - immunology; Neurosciences; Peptide Library; Peptides; Physiological aspects; Proteins; Receptors, Cell Surface - immunology; Recombinant Fusion Proteins - pharmacology; S100 Proteins - metabolism; technical-report; Tumor Escape - physiology; Tumor Microenvironment - drug effects; Tumor Microenvironment - immunology; Tumors; United States
• DOI: 10.1038/nm.3560
• EISSN: 1546-170X
• ISSN: 1078-8956

Using an adapted competitive peptide phage display platform, Hong Qin and colleagues identify new candidate peptides specifically binding myeloid-derived suppressor cells (MDSCs), with which they generate peptide-Fc fusion proteins (peptibodies). The peptibodies deplete intra-umoral MDSCs in several mouse tumor models, in addition to those in blood and spleen, with limited off-target activity and superiority over standard depletion methods. Validation of this approach for cell type–specific surface marker discovery identified S100A9 as a target on the surface of MDSCs.
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.