Browse > Article
http://dx.doi.org/10.7314/APJCP.2014.15.3.1321

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

Wang, Yong-Hua (Department of Urology, The Affiliated Hospital of Qingdao University)
Cao, Yan-Wei (Department of Urology, The Affiliated Hospital of Qingdao University)
Yang, Xue-Cheng (Department of Urology, The Affiliated Hospital of Qingdao University)
Niu, Hai-Tao (Department of Urology, The Affiliated Hospital of Qingdao University)
Sun, Li-Jiang (Department of Urology, The Affiliated Hospital of Qingdao University)
Wang, Xin-Sheng (Department of Urology, The Affiliated Hospital of Qingdao University)
Liu, Jing (Department of Pediatrics, The Affiliated Hospital of Qingdao University)
Publication Information
Asian Pacific Journal of Cancer Prevention / v.15, no.3, 2014 , pp. 1321-1326 More about this Journal
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 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.
Keywords
Toll-like receptor 4; B7-H1; urothelial bladder cancer; immune escape;
Citations & Related Records
Times Cited By KSCI : 1  (Citation Analysis)
연도 인용수 순위
1 Thompson RH, Kuntz SM, Leibovich BC, et al (2006). Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res, 66, 3381-5.   DOI
2 Qian Y, Deng J, Geng L, et al (2008). TLR4 signaling induces B7-H1 expression through MAPK pathways in bladder cancer cells. Cancer Invest, 26, 816-21.   DOI   ScienceOn
3 Song J, Abraham SN (2008). TLR-mediated immune responses in the urinary tract. Curr Opin Microbiol, 11, 66-73.   DOI
4 Sun Q, Liu Q, Zheng Y, et a1 (2008). Rapamycin suppresses TLR4-triggered IL-6 and PGE2 production of colon cancer cells by inhibiting TLR4 expression and NF-kappa B activation. Mol lmmunol, 45, 2929-36.
5 Tsujihashi H, Matsuda H, Uejima S, et al (1989). Immunoresponse of tissue infiltrating lymphocytes in bladder tumors. J Urol, 141, 1467-70.
6 Vabulas RM, Wagner H, Schild H (2002). Heat shock proteins as ligands of toll-like receptors. Curr Top Microbiol Immunol, 270, 169-84.
7 Zhang D, Zhang G, Hayden MS, et al (2004). A toll-like receptor that prevents infection by uropathogenic bacteria. Science, 303, 1522-6.   DOI   ScienceOn
8 Kaufman DS, Shipley WU, Feldman AS (2009). Bladder cancer. Lancet, 374, 239-49.   DOI   ScienceOn
9 Huang B, Zhao J, Li H, et al (2005). Toll-Like Receptors on Tumor Cells Facilitate Evasion of Immune Surveillance. Cancer Res, 65, 5009-14.   DOI   ScienceOn
10 Inman BA, Sebo TJ, Frigola X, et al (2007). PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCGinduced granulomata: associations with localized stage progression. Cancer, 109, 1499-505.   DOI
11 Iwai Y, Ishida M, Tanaka Y, et al (2002). Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA, 99, 12293-7.   DOI
12 Konishi J, Yamazaki K, Azuma M, et al (2004). B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res, 10, 5094-100.   DOI
13 Liu J, Hamrouni A, Wolowiec D, et al (2007). Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with IFN-{gamma} and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway. Blood, 110, 296-304.   DOI
14 Mukamel E, Shohat B, Servadio C (1982). Immunological profile of patients with transitional cell carcinoma of the bladder. Br J Urol, 54, 11-5.   DOI
15 Okudaira K, Hokari R, Tsuzuki Y, et al (2009). Blockade of B7-H1 or B7-DC induces an anti-tumor effect in a mouse pancreatic cancer model. Int J Oncol, 35, 741-9.
16 Patard JJ, Saint F, Velotti F, et al (1998). Immune response following intravesical Bacillus Calmette-Guerin instillations in superficial bladder cancer: a review. Urol Res, 26, 155-9.   DOI
17 Blank C, Brown I, Peterson AC, et al (2004). PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res, 64, 1140-5.   DOI
18 Ayari C, Bergeron A, LaRue H, et al (2011). Toll-like receptors in normal and malignant human bladders. J Urol, 2011, 185, 1915-21.   DOI
19 Babjuk M, Burger M, Zigeuner R, et al (2013). EAU Guidelines on Non-Muscle-invasive Urothelial Carcinoma of the Bladder: Update 2013. Eur Urol, 64, 639-53.   DOI   ScienceOn
20 Biragyn A, Ruffini PA, Leifer CA, et al (2002). Toll-like receptor 4-dependent activation of dendritic cells by beta-defensin 2. Science, 298, 1025-9.   DOI
21 Dong H, Strome SE, Salomao DR, et al (2002). Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med, 8, 793-800.
22 Elhag OA, Hu XJ, Wen-Ying Z, et al (2012). Reconstructed adeno-associated virus with the extracellular domain of murine PD-1 induces antitumor immunity. Asian Pac J Cancer Prev, 13, 4031-6.   과학기술학회마을   DOI
23 Ghebeh H, Mohammed S, Al-Omair A, et al (2006). The B7-H1 (PD-L1) T lymphocyte- inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors. Neoplasia, 8, 190-8.   DOI
24 Gong XH, Wang YH, Shao SX, et al (2013). Role of TLR4-signaling pathway in the immune evasion of bladder cancer and its mechanism. Chin J Cancer Prev Treat, 20, 1217-20.
25 Hasan A, Ghebeh H, Lehe C, et al (2011). Therapeutic targeting of B7-H1 in breast cancer. Expert Opin Ther Targets, 15, 1211-25.   DOI
26 Herr HW, Bean MA, Whitmore WF Jr (1976). Decreased ability of blood leukocytes from patients with tumors of the urinary bladder to act as stimulator cells in mixed leukocyte culture. Cancer Res, 36, 2754-60.
27 Loskog A, Ninalga C, Paul-Wetterberg G, et al (2007). Human bladder carcinoma is dominated by T-regulatory cells and Th1 inhibitory cytokines. J Urol, 177, 353-8.   DOI