Abstract
Currently, the effect of inflammation on tumorigenesis and progression has been widely noted. As a member of pattern recognition receptors, toll-like receptor 4 (TLR4) plays a pivotal role in tumor immune microenvironment and has been increasingly investigated. In the present study, we evaluated TLR4 expression and its association with programmed cell death ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC) tissues and assessed the predicting value of TLR4 on postoperative outcome. A total of 126 NSCLC patients receiving complete pulmonary resection and systematic lymph node dissection between April 2008 and August 2014 were enrolled. All the patients had integrated clinicopathological records and follow-up data. TLR4 and PD-L1 expression on NSCLC samples were determined by immunohistochemistry, and serum soluble TLR4 (sTLR4) levels were measured by enzyme-linked immunosorbent assay. Results showed that TLR4 expression level in cancer tissue was significantly higher than that in para-cancer tissue. Elevated TLR4 expression was significantly associated with histological type (adenocarcinoma higher than squamous cell carcinoma, P = 0.041), increased clinical TNM stage (P < 0.001), and presence of lymphatic invasion (P < 0.001). Besides, TLR4 expression level in cancer samples was inversely correlated with serum sTLR4 level in patients with early-stage NSCLC (r = −0.485, P = 0.003). TLR4 expression level was also positively correlated with the PD-L1 expression level (r = 0.545, P < 0.0001). Multivariate analysis showed that expression level of TLR4 was an independent prognostic factor and TLR4 overexpression indicated a poor overall survival and disease-free survival. Taken together, we conclude that expression of TLR4 in lung cancer is associated with PD-L1 and could predict the outcome of patients with NSCLC receiving pulmonary resection for cancer.
Highlights
The role of inflammation in tumorigenesis and progression has become evident, and it is generally accepted that an inflammatory microenvironment is an essential component of all tumors [1]
To determine the expression level of toll-like receptor 4 (TLR4) in lung cancers, immunohistochemical staining with antibody against TLR4 were performed to 126 cases of non-small cell lung cancer (NSCLC) tissues and 60 para-carcinoma tissues
Positive TLR4 immunostaining was mainly observed in the cytomembrane and cytoplasm of carcinoma cells (Figures 1A,B)
Summary
The role of inflammation in tumorigenesis and progression has become evident, and it is generally accepted that an inflammatory microenvironment is an essential component of all tumors [1]. As members of pattern recognition receptors, toll-like receptors (TLRs) play a crucial role in inflammation and innate immune function by recognizing pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS), lipopeptides, dsRNA, and bacterial DNA [4, 5]. As the first identified human Toll homolog, activation of toll-like receptor 4 (TLR4) in immune cells could trigger production of pro-inflammatory cytokines and other mediators against pathogens [6]. Except for immune cells, endothelial and various cancer cells express TLR4, and chronic stimulation of TLR4 could promote tumor initiation, growth, and tumor immune escape and induce chemoresistance through pro-inflammatory responses and antiapoptotic signals. The inverse correlation of cancer expressed TLR4, and patients’ outcome has been reported [7, 8]
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