免疫治療是目前癌症治療發展的熱門主題之一。目前已經開發了幾種類型的用於癌症治療的免疫療法，然而臨床上卻發現仍有一部份癌症患者對上述免疫療法臨床反應不佳。因此開發用於癌症治療的新型免疫治療具有重要的臨床意義。
癌症細胞會透過分泌犬尿氨酸 (kynurenine)以抑制 CD8+ T 細胞活化及誘導 CD4+ 調節T細胞活化，先前的研究證明吲哚胺 2,3-雙加氧酶 1 (IDO1) 和色氨酸 2,3-雙加氧酶 2 (TDO2) 在形成犬尿氨酸代謝路徑中速率決定步驟的酵素，且IDO1及TDO2的高度表現與癌症的較差總體存活率 (overall survival)有關，因此，IDO1和TDO2被認為是用於開發治療癌症的小分子免疫治療藥物的靶標。在這個研究中，我們的目標是找出有效抑制 IDO1/TDO2 雙酵素小分子抑制劑 （衍生自化合物 TD12 和 TD18）以用於開發癌症免疫療法。
在本篇研究中，首先我們利用西方墨點法和免疫螢光染色證實 SKOV3 （IDO1+ 卵巢癌細胞株）和A172 （TDO2+ 膠質母細胞瘤細胞株）細胞會表達 IDO1 或TDO2，為了建立用於藥物篩選的細胞平台，我們通過一系列參數調整包括細胞數量、色氨酸添加、干擾素-γ添加和實驗加藥流程設計成功建立篩選平台，而且透過由對照化合物 TD12 和 TD18（雙酵素 TDO2/IDO1 抑制劑）、epacadostat（選擇性 IDO1 抑制劑）和 680C91（選擇性 TDO2 抑制劑）證實了我們的藥物篩選平台能夠透過衡量犬尿氨酸的分泌以評估藥效，我們發現TC5、TC6、TC11及 TC12 作為部份雙酵素抑制劑，以及成功發現TC10和TC15為雙酵素抑制劑。
總結來說，我們建立了細胞模型的藥物篩選平台，並通過評估犬尿氨酸分泌抑制的百分比來檢測測試化合物的藥效，所以該篩選平台未來可以應用於篩選其他可能的IDO1/TDO2 抑制劑。

Immunotherapy currently is one of hot topics of cancer treatment development. Nowadays, several types of immuno-modulating agent have been developed. However, sub-populations of cancer patients have been found to be irresponsive to the above-mentioned immunotherapies. Therefore, it is clinical importance to develop a novel immunotherapy for cancer treatment.
Tumor cells secrete kynurenine to suppress CD8+ effector T cell activity and induce CD4+ T regulatory cell activity. Previous studies have shown that overexpressed indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2), which are enzymes responsible for catalyzing the rate-determining step of the kynurenine pathway, are related to poorer overall survival of cancer patients. Therefore, IDO1 and TDO2 are suggested as promising targets for development of anti-cancer small molecular drugs. In this study, we aim to identify potential dual IDO1/TDO2-targeting small molecular inhibitors (derived from the compound TD12 and TD18) for cancer treatment.
First, we demonstrated that either IDO1 or TOD2 were expressed in SKOV3 and A172 cells by the western blotting and immunofluorescence staining. To establish a cell-based kynurenine conversion assay for screening tested compounds in SKOV3 (IDO1+ ovarian cancer) and A172 (TDO2+ glioblastoma) cells, a series of parameter adjustments, including cell count, tryptophan addition, interferon-gamma addition, and treatment protocols, a cell-based kynurenine assay was carried out. The functionality of the assay was confirmed by the control compounds TD12 and TD18 (dual TDO2/IDO1 inhibitors), epacadostat (selective IDO1 inhibitor) and 680C91 (selective TDO2 inhibitor), which were able to inhibit kynurenine secretion in our screening platform. We identified TC5, TC6, TC11, and TC12 as partial dual enzyme inhibitors. Besides, we successfully identify TC10 and TC15 as dual enzyme inhibitors.
In conclusion, we set up the cell-based IDO1/TDO2 inhibitors screening platform and examined the potency of testing compounds on our platform by evaluating the percentage of kynurenine secretion inhibition. Therefore, our assay could be further be applied to screening other potential IDO1/TDO2 inhibitors for cancer treatment.

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