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.
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.
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TREM-1的一种新型的非配体依赖性肽抑制剂抑制了人类肺癌异种移植物中的肿瘤生长，并用脂多糖诱导的败血性休克延长小鼠的存活。
DOI：
10.1016/j.intimp.2014.05.001
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发表时间：
2014-07
影响因子：
5.6
通讯作者：
Sigalov AB
中科院分区：
文献类型：
--
作者：
Sigalov AB
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.
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影响因子：
15.3
作者：
Gibot, S;Kolopp-Sarda, MN;Béné, MC;Bollaert, PE;Lozniewski, A;Mory, F;Levy, B;Faure, GC
通讯作者：
Faure, GC
影响因子：
11.2
作者：
Aharinejad, S;Paulus, P;Abraham, D
通讯作者：
Abraham, D
影响因子：
3.1
作者：
Gibot, S;Buonsanti, C;Lévy, B
通讯作者：
Lévy, B
影响因子：
120.7
作者：
FISHER, CJ;DHAINAUT, JFA;STABLEIN, D
通讯作者：
STABLEIN, D
影响因子：
4.4
作者：
Dower, Ken;Ellis, Debra K.;Lin, Lih-Ling
通讯作者：
Lin, Lih-Ling