本文關(guān)鍵詞： 膀胱腫瘤 BCG TLR-4 B7-H1阻斷　出處：《青島大學》2017年碩士論文　論文類型：學位論文

【摘要】：目的:探討TLR-4和B7-H1在非肌層浸潤性膀胱癌(non muscle-invasive bladder cancer,NMIBC)卡介苗(Bacillus Calmette-Guérin,BCG)免疫治療失敗患者中的表達及臨床意義;構(gòu)建大鼠膀胱腫瘤模型,設(shè)置B7-H1阻斷與BCG聯(lián)合治療組,BCG組,B7-H1阻斷組及空白對照組,實驗結(jié)束后通過比較各組膀胱腫瘤的直徑及B7H1表達情況以評價各組治療方式的治療效果,以期證實阻斷B7-H1/PD-1通路能夠增強BCG治療高危膀胱癌的免疫效應(yīng)。方法:選取高危NMIBC術(shù)后BCG灌注治療失敗患者20例,采用免疫組化染色法檢測患者初發(fā)時和BCG治療失敗后膀胱癌組織中TLR-4和B7-H1蛋白的表達情況;構(gòu)建大鼠原位膀胱腫瘤動物模型,隨機分為B7-H1阻斷與BCG聯(lián)合治療組,BCG組,B7-H1阻斷組及空白對照組,各組處理完畢將各組大鼠處死解剖,觀察大鼠膀胱及膀胱內(nèi)腫瘤情況,測量各組腫瘤直徑,檢測各組膀胱癌細胞表面B7-H1分子表達情況。結(jié)果:BCG免疫治療高危NMIBC患者失敗后膀胱癌組織中TLR-4和B7-H1蛋白的表達較治療前均明顯增加,且二者表達呈明顯正相關(guān),差異均具有明顯的統(tǒng)計學意義;采用膀胱內(nèi)灌注N-甲基亞硝基脲(MNU)的方法,成瘤率高達95%。B7-H1阻斷與BCG聯(lián)合治療組與空白對照組之間膀胱腫瘤直徑差異明顯,比較有統(tǒng)計學意義(p0.05),BCG灌注組B7-H1分子表達水平明顯高于其他各組。結(jié)論:BCG免疫治療高危NMIBC失敗患者膀胱癌組織中存在著TLR-4和B7-H1表達上調(diào),而膀胱癌BCG免疫治療失敗可能與B7-H1表達上調(diào)介導(dǎo)的免疫逃逸機制有關(guān);BCG可誘導(dǎo)大鼠膀胱癌細胞B7-H1分子表達明顯升高。阻斷B7-H1/PD-1通路能增強BCG對膀胱腫瘤的治療效果。
[Abstract]:Objective: to investigate the role of TLR-4 and B7-H1 in non muscle-invasive bladder cancer of non-myometrial invasive bladder cancer. Expression and clinical significance of NMIBC- Bacillus Calmette-Gu 茅 rinn BCG in patients with failed immunotherapy; To establish the model of bladder tumor in rats, B7-H1 block and BCG combined treatment group were set up, the BCG-H1 blocking group and the blank control group were set up. After the experiment, we compared the diameter of bladder tumor and the expression of B7H1 in order to evaluate the therapeutic effect of each group. To prove that blocking B7-H1 / PD-1 pathway can enhance the immune effect of BCG in the treatment of high risk bladder cancer. Methods: 20 patients with failed BCG perfusion therapy after high-risk NMIBC were selected. Immunohistochemical staining was used to detect the expression of TLR-4 and B7-H1 protein in bladder cancer tissues at the beginning and after the failure of BCG treatment. The animal model of in situ bladder tumor in rats was established and divided into two groups randomly: B7-H1 block group and BCG combined treatment group (BCG-H1 blocking group and blank control group). The rats in each group were sacrificed and dissected. The bladder and intravesical tumor were observed and the tumor diameter was measured. The expression of B7-H1 on bladder cancer cells was detected. The expression of TLR-4 and B7-H1 protein in bladder cancer tissues were significantly increased after the failure of BCG immunotherapy in high-risk NMIBC patients. There was a significant positive correlation between them, and the difference was statistically significant. By intravesical instillation of N-methyl-nitroso (MNU-MNU), the tumorigenesis rate was as high as 95. B7-H1 block and BCG combined treatment group and blank control group, there was significant difference in bladder tumor diameter between the two groups. The comparison was statistically significant (P 0.05). The expression of B7-H1 in BCG perfusion group was significantly higher than that in other groups. The expression of TLR-4 and B7-H1 were up-regulated in bladder cancer tissues of patients with high risk NMIBC failure of BCG immunotherapy. However, the failure of BCG immunotherapy in bladder cancer may be related to the mechanism of immune escape mediated by up-regulation of B7-H1 expression. BCG could induce the increase of B7-H1 molecule expression in bladder cancer cells, and blocking B7-H1 / PD-1 pathway could enhance the therapeutic effect of BCG on bladder cancer.
【學位授予單位】：青島大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R737.14;R-332

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