Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.
Department of Anatomy, School of Medicine, Infectious Diseases Research Center, Gonabad University of Medical Sciences, Gonabad, Iran.
Int Immunopharmacol. 2023 May;118:110032. doi: 10.1016/j.intimp.2023.110032. Epub 2023 Mar 16.
Metabolic alterations occur commonly in tumor cells as a way to adapt available energetic sources for their proliferation, survival and resistance. Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular enzyme catalyzing tryptophan degradation into kynurenine. IDO1 expression shows a rise in the stroma of many types of human cancers, and it provides a negative feedback mechanism for cancer evasion from immunosurveillance. Upregulation of IDO1 correlates with cancer aggression, poor prognosis and shortened patient survival. The increased activity of this endogenous checkpoint impairs effector T cell function, increases regulatory T cell (Treg) population and induces immune tolerance, so its inhibition potentiates anti-tumor immune responses and reshapes immunogenic state of tumor microenvironment (TME) presumably through normalizing effector T cell activity. A point is that the expression of this immunoregulatory marker is upregulated after immune checkpoint inhibitor (ICI) therapy, and that it has inducible effect on expression of other checkpoints. These are indicative of the importance of IDO1 as an attractive immunotherapeutic target and rationalizing combination of IDO1 inhibitors with ICI drugs in patients with advanced solid cancers. In this review, we aimed to discuss about the impact of IDO1 on tumor immune ecosystem, and the IDO1-mediated bypass of ICI therapy. The efficacy of IDO1 inhibitor therapy in combination with ICIs in advanced/metastatic solid tumors is also a focus of this paper.
代谢改变在肿瘤细胞中很常见，是它们为增殖、存活和抵抗而适应可用能量来源的一种方式。吲哚胺 2,3-双加氧酶 1（IDO1）是一种细胞内酶，可催化色氨酸降解为犬尿氨酸。IDO1 在许多类型的人类癌症的基质中表达增加，它为癌症逃避免疫监视提供了负反馈机制。IDO1 的上调与癌症侵袭性、预后不良和患者生存时间缩短相关。这种内源性检查点的活性增加会损害效应 T 细胞功能，增加调节性 T 细胞（Treg）群体并诱导免疫耐受，因此其抑制作用增强了抗肿瘤免疫反应，并通过使效应 T 细胞的活性正常化来重塑肿瘤微环境（TME）的免疫原性状态。值得注意的是，这种免疫调节标志物的表达在免疫检查点抑制剂（ICI）治疗后上调，并且对其他检查点的表达具有诱导作用。这些表明 IDO1 作为一种有吸引力的免疫治疗靶点的重要性，并合理化了 IDO1 抑制剂与 ICI 药物在晚期实体瘤患者中的联合应用。在这篇综述中，我们旨在讨论 IDO1 对肿瘤免疫生态系统的影响，以及 IDO1 介导的 ICI 治疗旁路。IDO1 抑制剂联合 ICI 治疗晚期/转移性实体瘤的疗效也是本文的重点。
