title: Effect of TLR4 and B7-H1 on immune escape of urothelial bladder cancer and its clinical significance.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, China E-mail : doctorliujing@sina.com.
authors.forename: Yong-Hua
authors.initials: YH
authors.lastname: Wang
authors.forename: Yan-Wei
authors.initials: YW
authors.lastname: Cao
authors.forename: Xue-Cheng
authors.initials: XC
authors.lastname: Yang
authors.forename: Hai-Tao
authors.initials: HT
authors.lastname: Niu
authors.forename: Li-Jiang
authors.initials: LJ
authors.lastname: Sun
authors.forename: Xin-Sheng
authors.initials: XS
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
mesh_terms: D019138:Antibodies, Blocking / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000276:immunology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D008070:Lipopolysaccharides; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis*; D019139:Tumor Escape / Q000276:immunology; D001749:Urinary Bladder Neoplasms / Q000276:immunology* / Q000473:pathology; D019459:Urothelium / Q000473:pathology
chemical_list: D019138:Antibodies, Blocking; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D005419:Flavonoids; D008070:Lipopolysaccharides; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D047428:Protein Kinase Inhibitors; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one