Activation of Toll-like Receptor 4 on Tumor CellsIn vitroInhibits Subsequent Tumor GrowthIn vivo

Virginia Andreani,Gerardo Gatti,Mariana Maccioni,Virginia Rivero,Lucio Simonella

doi:10.1158/0008-5472.can-07-0079

Abstract

Although an eruption of information on the role of Toll-like receptor 4 (TLR4), the main receptor for bacterial lipopolysaccharide, in activating macrophages and dendritic cells has emerged, very little is known about the role of TLR4 present on epithelial cells from sterile environments like tumors. The main goal of this work was to investigate the consequences of TLR4 activation present on tumor cells in two different animal models of cancer: the Dunning rat prostate cancer and the B16 murine melanoma models. We show that (a) activating TLR4 signaling in two different tumor cell lines in vitro modifies the tumor outgrowth in vivo; (b) this effect is not due to a direct consequence of TLR4 signaling on the proliferation/apoptosis balance of the tumor cells; (c) the T-cell compartment is somehow involved in the described phenomenon because the inhibitory effect observed is not seen in athymic nude mice; and (d) tumor-infiltrating lymphocytes purified from tumors induced by TLR4-activated cells show strong induction of IFN gamma transcript in detriment of interleukin-10 transcript, suggesting a change in their functionality. We hypothesize that TLR4 signaling in tumor cells in vitro induces the expression of proinflammatory mediators, which could dramatically alter the maturation state of dendritic cells present at the site of inoculation, switching the type of immune response elicited against the tumor. These results open up new avenues for understanding the role of TLR4 in tumor cells and for identifying potential new therapy strategies for cancer.

Highlights

Toll-like receptors (TLR) conform a family of receptors that mediate the recognition of microbial/pathogen-associated molecular patterns that have been evolutionarily conserved in specific classes of microbes [1]
The main goal of this work was to investigate the consequences of Toll-like receptor 4 (TLR4) activation on tumor cells in two different animal models of cancer: the Dunning rat prostate cancer and the B16 murine melanoma models
We have recently shown that the rat prostate adenocarcinoma MAT-LU cells constitutively express TLR4 and CD14 and are perfectly capable of responding to LPS, activating nuclear factor nB (NF-nB) transcription factor, inducing inducible nitric oxide synthase expression, secreting nitric oxide, and up-regulating numerous chemokine genes like MCP1, MIP1a, IP10, RANTES, and IL-8 [19]

Summary

Introduction

Toll-like receptors (TLR) conform a family of receptors that mediate the recognition of microbial/pathogen-associated molecular patterns that have been evolutionarily conserved in specific classes of microbes [1]. TLR4, the first one described, recognizes the bacterial lipopolysaccharide (LPS), whereas members of the TLR9 subfamily, such as TLR7, TLR8, and TLR9, sense the microbial RNA and DNA Binding of these pathogen-associated molecular patterns to TLRs triggers a complicated series of events leading to an increased expression of proinflammatory genes [2]. The use of TLR ligands as adjuvants to reinforce the immune response against tumors is among the first and oldest strategies used in anticancer immunity This type of approaches has been empirically used long before TLRs were described, with the idea of activating TLRs-expressing antigen-presenting cells [18]. The same effect could be observed when B16 cells, capable of inducing melanomas once inoculated into C57BL/6 mice, were previously treated with LPS These results open up new avenues for understanding the role of TLRs, TLR4, in tumor cells and for identifying potential new therapy strategies for cancer

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