TLR3 Expression Induces Apoptosis in Human Non-Small-Cell Lung Cancer.

Francesca Bianchi,Chiara Camisaschi,Massimo Milione,Giovanni Centonze,Elda Tagliabue,Lucia Sfondrini,Andrea Balsari,Mauro Truini,Spyridon Alexiadis

doi:10.3390/ijms21041440

Abstract

The prognostic value of Toll-like receptor 3 (TLR3) is debated in cancer, differing between tumor types, methods, and cell types. We recently showed for the first time that TLR3 expression on early stage non-small-cell lung cancer (NSCLC) results associated with a good prognosis. Here, we provide experimental evidences explaining the molecular reason behind TLR3’s favorable prognostic role. We demonstrated that TLR3 activation in vitro induces apoptosis in lung cancer cell lines and, accordingly, that TLR3 expression is associated with caspase-3 activation in adenocarcinoma NSCLC specimens, both evaluated by immunohistochemistry. Moreover, we showed that TLR3 expression on cancer cells contributes to activate the CD103+ lung dendritic cell subset, that is specifically associated with processing of antigens derived from apoptotic cells and their presentation to CD8+ T lymphocytes. These findings point to the relevant role of TLR3 expression on lung cancer cells and support the use of TLR3 agonists in NSCLC patients to re-activate local innate immune response.

Highlights

To date, major efforts have focused on therapeutic strategies to overcome cancer resistance to immunosurveillance
To determine the relevance of Toll-like receptor 3 (TLR3)-induced apoptosis in lung cancer cells in driving good prognosis in non-small-cell lung cancer (NSCLC) patients, we explored the expression of cleaved caspase-3 in NSCLC specimens, highlighting that TLR3 expression correlates with cleaved caspase-3 expression in lung adenocarcinoma
TLR3-mediated mechanism of apoptosis in cancer cells is dependent on caspase-8 activation [10,17], which activates caspase-3 by proteolytic cleavage to amplify caspase-8 apoptosis initiation signals [18]

Summary

Introduction

Major efforts have focused on therapeutic strategies to overcome cancer resistance to immunosurveillance. TLR3, like other TLRs, is expressed on epithelial cells, including cancer cells of several histotypes [9]. Cancer cells respond to TLR3 ligands by secreting inflammatory cytokines, type I interferon (IFN I), and chemokines, which enhance the recruitment and activation of immune cells. TLR3 activation has been reported to mediate apoptosis in several cancer histotypes, primarily through an extrinsic pathway [10]. This unusual function of tumoral TLR3 has increased clinical interest in its targeting, prompting efforts to exploit the direct apoptotic effects of TLR3 on cancer cells [3]. Evidences on hepatocellular carcinoma (HCC), neuroblastomas or esophageal squamous cell carcinoma showed that TLR3 expression by the tumor parenchyma has been associated with a favorable prognosis (reviewed in [11,12]), and we recently observed that in early NSCLC, TLR3 expression on cancer cells is significantly associated with good overall survival [13]

Methods

Results

Conclusion