TLR3 Can Directly Trigger Apoptosis in Human Cancer Cells

Abstract

TLRs function as molecular sensors to detect pathogen-derived products and trigger protective responses ranging from secretion of cytokines that increase the resistance of infected cells and chemokines that recruit immune cells to cell death that limits microbe spreading. Viral dsRNA participate in virus-infected cell apoptosis, but the signaling pathway involved remains unclear. In this study we show that synthetic dsRNA induces apoptosis of human breast cancer cells in a TLR3-dependent manner, which involves the molecular adaptor Toll/IL-1R domain-containing adapter inducing IFN-β and type I IFN autocrine signaling, but occurs independently of the dsRNA-activated kinase. Moreover, detailed molecular analysis of dsRNA-induced cell death established the proapoptotic role of IL-1R-associated kinase-4 and NF-κB downstream of TLR3 as well as the activation of the extrinsic caspases. The direct proapoptotic activity of endogenous human TLR3 expressed by cancerous cells reveals a novel aspect of the multiple-faced TLR biology, which may open new clinical prospects for using TLR3 agonists as cytotoxic agents in selected cancers.

Increased expression of Toll-like receptor 3 in intrahepatic biliary epithelial cells at sites of ductular reaction in diseased livers

“…Exposure of pancreatic b cells to the combination of dsRNA and IFN-a, -b, or -c significantly increases apoptosis [27,28]. TLR3 can directly trigger apoptosis in human umbilical vein endothelial cells and cancer cells [29,30]. TLR3 plays a role in the development of hepatitis C-associated glomerulonephritis through the induction of mesangial cell apoptosis [31].…”

Toll-like receptors and immune regulation: implications for cancer therapy

“…Third, TLRs can directly stimulate the proliferation of CD4 þ and CD8 þ T cells as well as reverse the suppressive function of Treg cells (Crellin et al, 2005;Peng et al, 2005;Tabiasco et al, 2006). Finally, TLR9 and TLR3 agonists may also induce apoptosis of TLR-expressing tumor cells (Jahrsdorfer et al, 2005b;Salaun et al, 2006). However, as discussed above, optimal antitumor immunity requires robust enhancement of the effector T-cell response induced by tumor antigenic peptides and control or elimination of Treg cell-suppressive function.…”

Tumor stress, cell death and the ensuing immune response

“…Indeed, a direct proapoptotic activity of TLR3 agonists has been reported on TLR3-expressing breast tumor cell lines. 74 Moreover, in a mouse model of melanoma and glioma, adjuvant therapy with a TLR3 ligand (Poly I:C stabilized with poly-lysine and carboxymethylcellulose) could trigger the homing of tumor-specific CTLs to tumor beds. In the glioma model, this effect was obtained by the capacity of TLR3 to promote the secretion of IP-10 or and to induce the expression of 'very late antigen-4 0 (VLA-4, a heterodimer of a4 and b1 integrins) on CTLs 75 a change that augments the tropism of CTLs for the central nervous system.…”