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

Abstract

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

Ly6Clo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy

“…Figure 1C), which have not been reported in tumors after anti-VEGF therapy. These cells display a high level of CX3CR1, while Ly6C hi monocytes and Ly6G + neutrophils (hereafter referred to as neutrophils) express CCR2 and CXCR2, respectively (25,39,44) (Supplemental Figure 2B).…”

Targeting tumor-associated myeloid cells for cancer immunotherapy

“…1 In our recent publication, we demonstrated that MDSC are also present in the tumor microenvironment of mouse lymphomas and exert immunosuppressive and protumoral effects. 2 Taken together, these reports suggest that tumor-associated myeloid cells in B-cell lymphomas exist in different functional states and may collectively promote tumor growth and confer poor prognosis.…”

“…2 The peptides were further developed into therapeutic agents (peptibodies) that efficiently depleted splenic and intratumoral MDSC in tumor-bearing mice, but did not affect other proinflammatory cell types including dendritic cells, T, B, and NK lymphocytes, and immature myeloid cells in bone marrow, suggesting limited off-target activity. The peptibody treatment was associated with retardation of tumor growth in vivo highlighting the role of MDSC in tumorogenesis.…”

“…2 Through this proof-ofprinciple study, we established a technical platform of cell-specific marker discovery and a promising method to develop therapeutic reagents.…”

Nanoparticle design to induce tumor immunity and challenge the suppressive tumor microenvironment

“…Although research in the pathways involved in MDSC formation and maturation is still ongoing and novel potential targets to deplete MDSCs are being identified [126], successes have been obtained via cytokine therapy (local delivery of IL-12 or IFNα) or by the triggering of their TLRs 25 [127]. Once more, CpG ODN-delivering NPs were shown to have potential [122] as well as less known particulate adjuvants, such as very small size proteoliposomes (that combine outer membrane vesicles from N.meningitidis with a GM3 ganglioside) which were shown to modulate myeloid populations within the tumor environment, overcome T cell unresponsiveness and reduce tumor growth [128].…”