Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Sciences, Toyoake, Japan.
Graduate School of Health Sciences, Advanced Diagnostic System Research Laboratory, Fujita Health University, Toyoake, Japan.
Cancer Sci. 2019 Oct;110(10):3061-3067. doi: 10.1111/cas.14179. Epub 2019 Sep 25.
Tryptophan metabolism is important to induce immune tolerance in tumors. To date, 3 types of tryptophan-metabolizing enzymes have been identified: indoleamine 2,3-dioxygenase 1 and 2 (IDO1 and IDO2) and tryptophan 2,3-dioxygenase 2. Numerous studies have focused on IDO1 as its expression is enhanced in various cancers. Recently, IDO2 has been identified as a tryptophan-metabolizing enzyme that is involved in several immune functions and expressed in cancers such as pancreatic cancer. However, the biological role of IDO2 in the induction of immune tolerance in tumors has not yet been reported. In the present study, we examined the effects of Ido2 depletion on tumor growth in a mouse model of Lewis lung carcinoma by using Ido2-knockout mice. Ido2-knockout mice had reduced tumor volumes compared to WT mice. Furthermore, Ido2 depletion altered the tumor microenvironment, such as tryptophan accumulation and kynurenine reduction, leading to enhancement of immune cell invasion. Finally, enzyme-linked immunospot assay revealed that Ido2 depletion enhanced γ-interferon secretion in the tumor. In conclusion, Ido2 is an important immune regulator in the tumor microenvironment. Our data indicate that IDO2 is a potential target for cancer treatment and drug development.
色氨酸代谢对于诱导肿瘤中的免疫耐受很重要。迄今为止，已经鉴定出 3 种色氨酸代谢酶：吲哚胺 2,3-双加氧酶 1 和 2（IDO1 和 IDO2）和色氨酸 2,3-双加氧酶 2。许多研究都集中在 IDO1 上，因为它在各种癌症中的表达增强。最近，IDO2 被鉴定为一种参与多种免疫功能的色氨酸代谢酶，并在胰腺癌等癌症中表达。然而，IDO2 在诱导肿瘤免疫耐受中的生物学作用尚未报道。在本研究中，我们通过使用 IDO2 敲除小鼠来检查 Ido2 耗竭对 Lewis 肺癌小鼠模型中肿瘤生长的影响。与 WT 小鼠相比，IDO2 敲除小鼠的肿瘤体积减小。此外，IDO2 耗竭改变了肿瘤微环境，例如色氨酸积累和犬尿氨酸减少，导致免疫细胞浸润增强。最后，酶联免疫斑点分析显示，IDO2 耗竭增强了肿瘤中的γ-干扰素分泌。总之，IDO2 是肿瘤微环境中的重要免疫调节剂。我们的数据表明，IDO2 是癌症治疗和药物开发的潜在靶点。
