A novel ligand-independent peptide inhibitor of TREM-1 suppresses tumor growth in human lung cancer xenografts and prolongs survival of mice with lipopolysaccharide-induced septic shock.
Triggering receptor expressed on myeloid cells-1 (TREM-1) amplifies the inflammatory response and plays a role in cancer and sepsis. Inhibition of TREM-1 by short hairpin RNA (shRNA) in macrophages suppresses cancer cell invasion in vitro. In the clinical setting, high levels of TREM-1 expression on tumor-associated macrophages are associated with cancer recurrence and poor survival of patients with non-small cell lung cancer (NSCLC). TREM-1 upregulation on peritoneal neutrophils has been found in human sepsis patients and in mice with experimental lipopolysaccharide (LPS)-induced septic shock. However, the precise function of TREM-1 and the nature of its ligand are not yet known. In this study, we used the signaling chain homooligomerization (SCHOOL) model of immune signaling to design a novel, ligand-independent peptide-based TREM-1 inhibitor and demonstrated that this peptide specifically silences TREM-1 signaling in vitro and in vivo. Utilizing two human lung tumor xenograft nude mouse models (H292 and A549) and mice with LPS-induced sepsis, we show for the first time that blockade of TREM-1 function using non-toxic and non-immunogenic SCHOOL peptide inhibitors: 1) delays tumor growth in xenograft models of human NSCLC, 2) prolongs survival of mice with LPS-induced septic shock, and 3) substantially decreases cytokine production in vitro and in vivo. In addition, targeted delivery of SCHOOL peptides to macrophages utilizing lipoprotein-mimicking nanoparticles significantly increased peptide half-life and dosage efficacy. Together, the results suggest that ligand-independent modulation of TREM-1 function using small synthetic peptides might be a suitable treatment for sepsis and NSCLC and possibly other types of inflammation-associated disorders.
SignaBlok, Inc., Shrewsbury, MA 01545, USA. Electronic address: Sigalov@signablok.com.
Alexander B
AB
Sigalov
D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008075:Lipoproteins, HDL / Q000008:administration & dosage* / Q000737:chemistry; D008175:Lung Neoplasms / Q000188:drug therapy*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000737:chemistry; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors; D012772:Shock, Septic / Q000139:chemically induced / Q000188:drug therapy*; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D016207:Cytokines; D008070:Lipopolysaccharides; D008075:Lipoproteins, HDL; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D011971:Receptors, Immunologic; C517262:TREM1 protein, mouse; D000073871:Triggering Receptor Expressed on Myeloid Cells-1
HDL nanoparticles; Non-small cell lung cancer; Sepsis; TREM-1 receptor; Targeted delivery; Therapeutic SCHOOL peptides