IDO1 is an immunomodulatory enzyme responsible for tryptophan catabolism. Its expression in immune cells, especially the DCs, has attracted attention because it leads to tryptophan depletion at the immunological synapse, thereby causing T-cell anergy and immune evasion by the tumor cells. Cancer cells also overexpress IDO1. Immunotherapy targeting IDO1 has been one of the focus areas in cancer biology, but lately studies have identified non-immune related functions of IDO1 leading to a paradigm shift with regard to IDO1 function in the context of tumor cells. In this study, we show that PDAC tissues and PDAC cells overexpress IDO1. The expression level is reciprocally related to overall patient survival. We further show that carbidopa, an FDA-approved drug for Parkinson's disease as well as an AhR agonist, inhibits IDO1 expression in PDAC cells. Using athymic nude mice, we demonstrate that carbidopa-mediated suppression of IDO1 expression attenuates tumor growth. Mechanistically, we show that AhR is responsible for carbidopa-mediated suppression of IDO1, directly as a transcription factor and indirectly by interfering with the JAK/STAT pathway. Overall, targeting IDO1 not only in immune cells but also in cancer cells could be a beneficial therapeutic strategy for PDAC and potentially for other cancers as well and that carbidopa could be repurposed to treat cancers that overexpress IDO1.

中文翻译：

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芳烃受体激活剂卡比多巴抑制胰腺癌中 IDO1 的表达并减少肿瘤生长

IDO1 是一种负责色氨酸分解代谢的免疫调节酶。它在免疫细胞，尤其是 DCs 中的表达引起了人们的关注，因为它导致免疫突触处的色氨酸耗尽，从而导致 T 细胞无能和肿瘤细胞的免疫逃避。癌细胞也过表达 IDO1。针对 IDO1 的免疫疗法一直是癌症生物学的重点领域之一，但最近的研究已经确定了 IDO1 的非免疫相关功能，导致肿瘤细胞背景下 IDO1 功能的范式转变。在这项研究中，我们显示 PDAC 组织和 PDAC 细胞过表达 IDO1。表达水平与患者的总生存率呈反比关系。我们进一步表明卡比多巴，一种 FDA 批准的帕金森病药物以及 AhR 激动剂，抑制 PDAC 细胞中 IDO1 的表达。使用无胸腺裸鼠，我们证明卡比多巴介导的 IDO1 表达抑制减弱了肿瘤生长。从机制上讲，我们表明，AhR 负责卡比多巴介导的 IDO1 抑制，直接作为转录因子，间接通过干扰 JAK/STAT 通路。总体而言，不仅针对免疫细胞而且针对癌细胞中的 IDO1 可能是 PDAC 以及其他癌症的有益治疗策略，并且卡比多巴可以重新用于治疗过度表达 IDO1 的癌症。直接作为转录因子，间接通过干扰 JAK/STAT 通路。总体而言，不仅针对免疫细胞而且针对癌细胞中的 IDO1 可能是 PDAC 以及其他癌症的有益治疗策略，并且卡比多巴可以重新用于治疗过度表达 IDO1 的癌症。直接作为转录因子，间接通过干扰 JAK/STAT 通路。总体而言，不仅针对免疫细胞而且针对癌细胞中的 IDO1 可能是 PDAC 以及其他癌症的有益治疗策略，并且卡比多巴可以重新用于治疗过度表达 IDO1 的癌症。