Interferon-Induced IDO1 Mediates Radiation Resistance and Is a Therapeutic Target in Colorectal Cancer
Interferon-Induced IDO1 Mediates Radiation Resistance and Is a Therapeutic Target in Colorectal Cancer
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DOI：
10.1158/2326-6066.cir-19-0282
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发表时间：
2020-04-01
影响因子：
10.1
通讯作者：
Ciorba, Matthew A.
中科院分区：
文献类型：
--
作者：
Chen, Baosheng;Alvarado, David M.;Ciorba, Matthew A.
结直肠癌是全球死亡的主要原因之一。化疗和放疗仍然是局部晚期疾病的标准治疗方法，目前的免疫靶向治疗仅适用于一小部分患者。免疫肿瘤学靶点吲哚胺2,3双加氧酶1 （IDO1）的表达与结直肠癌的不良临床结果相关，但作为潜在的治疗靶点尚未得到充分研究。在本研究中，我们研究了IDO1通路与结直肠癌放疗之间的相互作用。我们使用人和小鼠结直肠癌细胞系、类器官、小鼠同基因结直肠癌肿瘤移植模型和放疗患者的结直肠癌组织。IDO1活性被临床IDO1抑制剂epacadostat和基因破坏阻断。我们发现辐射通过I型和II型IFN信号诱导IDO1在结直肠癌中过表达。IDO1酶活性直接影响结直肠癌的辐射敏感性。IDO1抑制使结直肠癌对辐射诱导的细胞死亡敏感，而IDO1代谢物犬尿氨酸促进辐射保护。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，促进了辐射场外肿瘤的外显效应。相反，IDO1阻断可以保护正常小肠上皮免受辐射毒性的影响，并加速辐射引起的体重减轻的恢复，表明在限制副作用方面发挥作用。这些数据表明，IDO1抑制增强了结直肠癌放疗的有效性。该研究结果还为IDO1抑制剂作为局部晚期散发性和结肠炎相关结直肠癌患者放射辅助治疗的研究提供了理论基础和机制见解。
Colorectal cancer 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 immunooncology target indoleamine 2,3 dioxygenase 1 (IDO1) is associated with poor colorectal cancer clinical outcomes but is understudied as a potential treatment target. In this study, we examined the interaction between the IDO1 pathway and radiotherapy in colorectal cancer. We used human and mouse colorectal cancer cell lines, organoids, mouse syngeneic colorectal cancer tumor graft models, and colorectal cancer tissues from patients who received radiotherapy. IDO1 activity was blocked using the clinical IDO1 inhibitor epacadostat and by genetic disruption. We found that radiation induced IDO1 overexpression in colorectal cancer through type I and II IFN signaling. IDO1 enzymatic activity directly influenced colorectal cancer radiation sensitivity. IDO1 inhibition sensitized colorectal cancer 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 radiotherapy 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.