TLR1/2 Specific Small‐Molecule Agonist Suppresses Leukemia Cancer Cell Growth by Stimulating Cytotoxic T Lymphocytes. Issue 10 (27th March 2019)

• Record Type: Journal Article
• Authors: Cen, Xiaohong; Zhu, Gengzhen; Yang, Junjie; Yang, Jianjun; Guo, Jiayin; Jin, Jiabing; Nandakumar, Kutty Selva; Yang, Wei; Yin, Hang; Liu, Shuwen; Cheng, Kui
• Is Part Of: Advanced science. Volume 6:Issue 10(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-03-27
• Subjects: agonist -- CD8+ T -- leukemia -- Toll‐like receptor 2 (TLR2) -- tumor immunity; Science -- Periodicals; 505
• DOI: 10.1002/advs.201802042
• Languages: English
• ISSNs: 2198-3844

Abstract

Abstract: Toll‐like receptor 2 (TLR2) expressed on antigen presenting cells evokes a series of critical cytokines, which favor the development of tumor‐specific cytotoxic T lymphocytes (CTLs). Therefore, TLR2 represents an attractive cancer immunotherapeutic target. Here, a synthetic library of 14 000 compounds together with a series of newly developed compounds for NF‐κB activation using HEK‐Blue hTLR2 cells is initially screened. Following further screening in a variety of cells including HEK‐Blue hTLRs reporter cells, murine, and human macrophage cell lines, a potent small molecule agonist 23 (SMU‐Z1) is identified, which specifically activates TLR2 through its association with TLR1, with a EC50 of 4.88 ± 0.79 × 10 −9 m . Toxicology studies, proinflammatory cytokines (e.g., TNF‐α, IL‐1β, IL‐6, and nitric oxide) and target‐protein based biophysical assays demonstrate the pharmacologically relevant characteristics of SMU‐Z1. In addition, SMU‐Z1 promotes murine splenocyte proliferation and upregulates the expression of CD8 + T cells, NK cells and DCs, which results in a significant antitumor effect in a murine leukemia model. Finally, the induced tumors in three out of seven mice disappear after administration of SMU‐Z1. Our studies thus identify a novel and potent TLR1/2 small molecule agonist, which displays promising immune adjuvant properties and antitumor immunity. Abstract : A potent small‐molecule compound SMU‐Z1, which specifically activates Toll‐like receptor (TLR2) through its association with TLR1, is identified. SMU‐Z1 promotes murine splenocyte proliferation and upregulates CD8 + T cells, natural killer (NK) cells, and dendritic cells (DCs), which in turn enhances significant antitumor immunity against murine leukemia in vivo.