Abstract
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 regulation of tumor immunity. It has been shown that urothelial bladder cancer (UBC) patients can manifest tumoral immune 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 investigate the effect of TLR4 and B7-H1 on immune escape of UBC. Bladder cancer T24 cells were pre-incubated with LPS and co-cultured with tumor specific CTLs. CTL cytotoxicity and apoptosis rates were measured by MTT assay and flow cytometry, respectively. The effects of an ERK inhibitor on B7-H1 expression and CTL cytotoxicity against T24 cells were also evaluated. In addition, TLR4, B7-H1 and PD-1 protein expression was analyzed by immunohistochemistry in 60 UBC specimens and 10 normal urothelia. TLR4 activation protected T24 cells from CTL killing via B7-H1 overexpression. However PD98059, an inhibitor of ERK, enhanced CTL killing of T24 cells by reducing B7-H1 expression. TLR4 expression was generally decreased in UBC specimens, while B7-H1 and PD-1 were greatly overexpressed. Moreover, expression of both B7-H1 and PD-1 was significantly associated with UICC stage and WHO grade classification. TLR4 and B7-H1 may contribute to immune escape of UBC. Targeting B7-H1 or the ERK pathway may offer new immunotherapy strategies for bladder cancer.
Highlights
Urothelial bladder cancer (UBC) is the most common malignancy of the urinary tract and the 7th most common cancer in men and the 17th in women (Babjuk et al, 2013)
To evaluate the significance of Toll-like receptor 4 (TLR4) activation and B7-H1 expression in T24 cells, we studied T24 cells cocultured with tumor specific CTLs and tested CTLs cytotoxicity and apoptosis rate
Previous studies demonstrated that MAPK pathway, especially ERK pathway was involved in LPS-induced B7-H1 expression in bladder cancer cells
Summary
Urothelial bladder cancer (UBC) is the most common malignancy of the urinary tract and the 7th most common cancer in men and the 17th in women (Babjuk et al, 2013). It has been shown that B7-H1 can inhibit immune responses by inducing T-cell apoptosis, impairing cytokine production, and diminishing the cytotoxicity of activated T cells and may endow tumors with a mechanism to escape host immune destruction (Dong et al, 2002; Iwai et al, 2002; Blank et al, 2004). Qian et al demonstrated that MAPK pathway, especially ERK pathway was involved in LPS-induced B7-H1 expression in bladder cancer cells and inferred that blocking of B7-H1 or ERK pathway may be new targeted molecular strategies for bladder cancer (Qian et al, 2008). All these results implied the associations of TLR4 and B7-H1 with UBC-
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