2016-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/658355摘要：泌尿上皮癌(urothelial carcinoma)的發生率為每年每十萬人中11.6人次，是台灣地區前十大常見的惡性腫瘤。台灣與巴爾幹半島地區同為全世界上泌尿道(腎盂及輸尿管)泌尿上皮癌發生率最高的地區，且數倍於歐美等西方國家。從近幾年的研究顯示，台灣上泌尿道泌尿上皮癌顯與馬兜鈴酸相關。馬兜鈴酸是一個致突變率極高的化學物質，在台灣的病人群中確實也發現有較多的基因突變。這些具有多處突變的泌尿上皮癌腫瘤，會引起怎樣的免疫反應，又其對於免疫治療的反應如何，則是本計畫所要深入探討的。針對非肌肉侵犯型的膀胱泌尿上皮癌及原位癌的病人，經尿道膀胱腫瘤刮除後的卡介苗膀胱灌注治療，是目前的標準治療方式。如今，我們也發現全身性免疫治療對於治療泌尿上皮癌，扮演著越來越吃重的角色。截至目前為止，包括IL-2，IFN-α，ipilimumab，anti-programmed cell death (PD-1)/anti-programmed cell death-ligand 1 (PD-L1)抑制劑均已被應用於腫瘤的治療。進一步研究發現，基因修補缺失的腫瘤與越多基因突變的腫瘤，接受PD-1 抑制劑的效果可能越好。延伸至台灣的泌尿上皮癌，馬兜鈴酸引起的高突變頻率腫瘤，對於免疫治療是否有著不同於其他腫瘤的好結果呢?在本次計畫中，我們首先利用過去建構的台灣上泌尿道泌尿上皮癌腫瘤基因突變位點與型態，製作neoantigen組庫。檢定那些neoantigen次群可以有效偵測出病人對於腫瘤的免疫反應。並透過與對照組的比對，檢定病人T細胞組庫的特徵。最後，整合免疫組庫、基因突變頻率與樣態、尿液加合物的資料，建構一個可以預測病人預後、藥物反應、與診斷疾病的生物指標模組。此外，我們也將檢定基因突變的不同，與病人組織和血液中免疫細胞型態的相關性，並分析他們與治療成效的關係。<br> Abstract: Urothelial carcinoma (UC) is the 9th leading malignancy in Taiwan, and the incidence is about 11.6/100,000 person-year. Both Taiwan and Balkan areas have the highest incidence of the upper urinary tract urothelial carcinoma (UTUC) around the world. Recent published studies revealed strong evidence between aristolochic acid and UTUC. Aristolochic acid was proven to be a very potent carcinogen which causes high mutation frequency in cancer cells. Similarly, our previous work identified higher mutation frequency in Taiwan UTUC patients compared to that in western countries. Therefore, we wonder to study immunologic reaction, and response to immunologic therapy in the UC with high tumor mutation load. Intravesical immunotherapy with BCG is one of standard treatments for post-resection non-muscle invasive bladder UC. Recently, immunotherapy becomes more and more important for UC. Immunotherapeutic agents, such as IL-2, IFN-α, ipilimumab, anti-programmed cell death (PD-1/ PD-L1) inhibitors, were gradually applied for managing tumors. Furthermore, mismatch repair-deficiency and high mutation rate were associated with good response to PD-1 inhibitors. Inspired from the above evidence, we try to answer whether aristolochic acid induced UTUC or UC which contain high mutation load would have better response of immunotherapy compared to other malignancies.In this study, we will establish a neoantigen bank based on our previous publication in terms of mutation location and pattern. Secondly, we evaluate the immunological response to each neoantigen subgroup in our UC patients. Thirdly, signature of T cell receptor repertoire will be confirmed by comparison between UC patients and normal controls. Fourthly, we plan to construct a biomarker model predicting patient outcomes and diagnosis of UC by combining signature of neoantigen subgroup, TCR repertoire, tumor mutation location and pattern, and adductomics in urine. In addition, we will also exam the relationship among mutation sites, patterns, circulatory immune pattern, local tissue immune presentation and outcomes.泌尿上皮癌馬兜鈴酸免疫治療免疫組庫加何物突變負荷urothelial carcinomaaristolochic acidimmune therapyimmune repertoireadductmutation load