Colorectal cancer (CRC) is a major cause of mortality worldwide. Chemotherapy and radiation remain standard treatment for locally advanced disease, with current immune-targeting therapies applying to only a small subset of patients. Expression of the immuno-oncology target indoleamine 2,3 dioxygenase 1 (IDO1) is associated with poor CRC clinical outcomes but is understudied as a potential treatment target. In this study, we examined the interaction between the IDO1 pathway and radiation therapy in CRC. We used human and mouse CRC cell lines, organoids, mouse syngeneic CRC tumor graft models, and CRC tissues from patients who received radiation therapy. IDO1 activity was blocked using the clinical IDO1 inhibitor epacadostat and by genetic disruption. We found that radiation-induced IDO1 overexpression in CRC through Type I and II interferon signaling. IDO1 enzymatic activity directly influenced CRC radiation sensitivity. IDO1 inhibition sensitized CRC to radiation-induced cell death, whereas the IDO1 metabolite kynurenine promoted radioprotection. IDO1 inhibition also potentiated Th1 cytokines and myeloid cell-modulating factors in the tumor microenvironment and promoted an abscopal effect on tumors outside the radiation field. Conversely, IDO1 blockade protected the normal small intestinal epithelium from radiation toxicity and accelerated recovery from radiation-induced weight loss, indicating a role in limiting side-effects. These data demonstrated that IDO1 inhibition potentiates radiation therapy effectiveness in colorectal cancer. The findings also provide rationale and mechanistic insight for the study of IDO1 inhibitors as adjuvant therapy to radiation in patients with locally advanced sporadic and colitis-associated colorectal cancer.

中文翻译：

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干扰素诱导的IDO1介导抗辐射性，是大肠癌的治疗靶标。

结肠直肠癌（CRC）是全世界死亡的主要原因。化学疗法和放射疗法仍然是局部晚期疾病的标准治疗方法，目前的免疫靶向疗法仅适用于一小部分患者。免疫肿瘤学靶标吲哚胺2,3双加氧酶1（IDO1）的表达与CRC临床结果差有关，但被低估为潜在的治疗靶标。在这项研究中，我们检查了IDO1途径与CRC放射治疗之间的相互作用。我们使用了人类和小鼠CRC细胞系，类器官，小鼠同基因CRC肿瘤移植模型以及来自接受放射治疗的患者的CRC组织。IDO1活性被临床IDO1抑制剂依帕妥司他和基因破坏所阻断。我们发现通过I型和II型干扰素信号传导在CRC中辐射诱导的IDO1过表达。IDO1的酶活性直接影响CRC辐射敏感性。IDO1抑制使CRC对辐射诱导的细胞死亡敏感，而IDO1代谢产物犬尿氨酸促进放射防护。IDO1抑制还增强了肿瘤微环境中的Th1细胞因子和髓样细胞调节因子，并促进了辐射场外肿瘤的抽象作用。相反，IDO1阻断可保护正常的小肠上皮免于辐射毒性，并加速从辐射引起的体重减轻中恢复，表明在限制副作用方面发挥了作用。这些数据证明IDO1抑制增强了结直肠癌的放射治疗效果。