Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzing the conversion of tryptophan (Trp) to kynurenine (Kyn) in kynurenine pathway (KP) is involved in the immunosuppression in pancreatic cancer (PC), but the value of IDO1 as an independent prognostic marker for PC is uncertain. Moreover, the correlation between tryptophan 2,3-dioxygenase (TDO), an isozyme of IDO1, and PC is largely unknown. Using TCGA database, the correlation between IDO1 and/or TDO expression and PC patients’ survival was analyzed. The expressions of IDO1 and TDO in PC cells and PC mice were examined. The effects of IDO1, TDO or dual inhibition on IDO1 and TDO effector pathway (Aryl hydrocarbon receptor, AhR) and on migration and invasion of PC cells were investigated. The block effect of IDO1/TDO dual inhibitor RY103 on KP was evaluated. The preclinical efficacy of RY103 and its immunomodulatory effect on KPIC orthotopic PC mice and Pan02 tumor-bearing mice were explored. Results showed that IDO1/TDO co-expression is an independent prognostic marker for PC. RY103 can significantly block KP and target Kyn-AhR pathway to blunt the migration and invasion of PC cells, exhibit preclinical efficacy and ameliorate IDO1/TDO-mediated immunosuppression in PC mice.

吲哚胺 2,3-双加氧酶 1 (IDO1) 在犬尿氨酸途径 (KP) 中催化色氨酸 (Trp) 转化为犬尿氨酸 (Kyn) 参与胰腺癌 (PC) 的免疫抑制，但 IDO1 作为独立预后指标的价值PC 的标记不确定。此外，IDO1 的同工酶色氨酸 2,3-双加氧酶 (TDO) 与 PC 之间的相关性在很大程度上是未知的。使用 TCGA 数据库，IDO1和/或TDO之间的相关性分析表达和PC患者的存活率。检测了PC细胞和PC小鼠中IDO1和TDO的表达。研究了 IDO1、TDO 或双重抑制对 IDO1 和 TDO 效应途径（芳烃受体，AhR）以及对 PC 细胞迁移和侵袭的影响。评价了IDO1/TDO双重抑制剂RY103对KP的阻断作用。探讨了RY103的临床前疗效及其对KPIC原位PC小鼠和Pan02荷瘤小鼠的免疫调节作用。结果表明，IDO1/TDO 共表达是 PC 的独立预后标志物。RY103 可显着阻断 KP 并靶向 Kyn-AhR 通路，从而抑制 PC 细胞的迁移和侵袭，表现出临床前疗效并改善 IDO1/TDO 介导的 PC 小鼠免疫抑制。