Effect of TLR4 and B7-H1 on Immune Escape of Urothelial Bladder Cancer and its Clinical Significance

Abstract

Background/Aim: Toll-like receptor 4 (TLR4) and B7-H1, both normally expressed restricted to immune cells,are found to be aberrantly expressed in a majority of human tumors and may play important roles in regulationof tumor immunity. It has been shown that urothelial bladder cancer (UBC) patients can manifest tumoralimmune escape which may be a potential critical factor in tumor pathogenesis and progression. However, so far,the mechanisms of UBC-related immune escape have not been clarified. The aim of this study was to investigatethe effect of TLR4 and B7-H1 on immune escape of UBC. <br/><b>Methods</b>: Bladder cancer T24 cells were pre-incubatedwith LPS and co-cultured with tumor specific CTLs. CTL cytotoxicity and apoptosis rates were measured by MTTassay and flow cytometry, respectively. The effects of an ERK inhibitor on B7-H1 expression and CTL cytotoxicityagainst T24 cells were also evaluated. In addition, TLR4, B7-H1 and PD-1 protein expression was analyzed byimmunohistochemistry in 60 UBC specimens and 10 normal urothelia. <br/><b>Results</b>: TLR4 activation protected T24cells from CTL killing via B7-H1 overexpression. However PD98059, an inhibitor of ERK, enhanced CTL killingof T24 cells by reducing B7-H1 expression. TLR4 expression was generally decreased in UBC specimens, whileB7-H1 and PD-1 were greatly overexpressed. Moreover, expression of both B7-H1 and PD-1 was significantlyassociated with UICC stage and WHO grade classification. <br/><b>Conclusions</b>: TLR4 and B7-H1 may contribute toimmune escape of UBC. Targeting B7-H1 or the ERK pathway may offer new immunotherapy strategies forbladder cancer.