TLR1/2 Specific Small‐Molecule Agonist Suppresses Leukemia Cancer Cell Growth by Stimulating Cytotoxic T Lymphocytes

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 EC 50 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.

Combining IL-2-based immunotherapy with commensal probiotics produces enhanced antitumor immune response and tumor clearance

“…42 43 Here, in tumor-bearing mice, it was first found that tumor suppression efficacy of Amuc was partly mediated through TLR2 signaling pathway, which is consistent with other reports that activation of TLR2 was capable of remodeling tumor immune microenvironment and, in turn, inducing significant tumor shrink. [44][45][46][47][48] In addition, our results are also in line with the previous studies that Amuc could specially stimulate ex vivo TLR2expressing cells to prevent the development of obesity and type 2 diabetes. 24 As an active part of AKK to produce antitumor effects, Amuc can also be used as a potential adjuvant for cancer immunotherapy.…”

Macrophage activation on “phagocytic synapse” arrays: Spacing of nanoclustered ligands directs TLR1/2 signaling with an intrinsic limit

“…The quantitative relationship between the spatial arrangement of Pam 3 nanodisks and macrophage immune responses we found in this study indicates that it is possible to modulate immune responses by engineering the spatial organization of cell receptors. Recent studies have shown potential applications of Pam 3 ( 61 ) and other TLR1/2 agonists ( 62 – 64 ) as adjuvants for tumor immunotherapy. It was suggested that coactivation of TLR1/2 together with FcRs may provide the strong pro-inflammatory responses needed to reverse the tumor immunosuppressive environment in antibody-based cancer immunotherapy ( 20 , 65 , 66 ).…”

The Anti-Inflammatory Effect of Taurine on Cardiovascular Disease

“…As demonstrated by animal TLR knockout models [ 90 , 91 , 92 , 93 , 94 , 95 , 96 ] and studies involving TLR deficiency [ 97 , 98 ] and polymorphisms in humans [ 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 ], absence or improper function of TLRs can attenuate inflammation, influence disease susceptibility, and restore homeostatic balance. Thus, TLRs have become targets of TLR inhibition therapies [ 112 , 113 , 114 , 115 , 116 ]. This review will discuss the potential inhibitory and immunomodulating abilities of taurine and its metabolites on TLR signal transduction, which may make them suitable anti-inflammatory therapeutics in CVD pathologies.…”

“…Deficiencies and polymorphisms have shown beneficial results in disease severity and susceptibility [ 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 ]. Thus, TLRs have become targets of pharmaceuticals and small molecules treatments in TLR inhibition therapies [ 112 , 113 , 114 , 115 , 116 ]. TLRs exert damaging effects through chronic unregulated inflammation through the TLR/MyD88/NF- K pathway [ 80 ].…”