Research Group Epigenetics, Metabolism and Longevity, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany.
Department of Pediatrics, Rostock University Medical Center, Rostock, Germany.
Front Immunol. 2019 Jul 30;10:1801. doi: 10.3389/fimmu.2019.01801. eCollection 2019.
Immunooncology is still a growing area in cancer therapy. Drugs within this therapeutic approach do not directly target/attack the tumor but interfere with immune checkpoints and target or reprogram key metabolic pathways critical for anti-cancer immune defense. Indolamine 2,3-dioxygenase 1 (IDO1) and the tryptophan (TRP)-kynurenine pathway were identified as critical mechanisms in cancer immune escape and their inhibition as an approach with promising therapeutic potential. Particularly, a multitude of IDO1 inhibiting tryptophan analogs are widely applied in several clinical trials. However, this therapy results in a variety of implications for the patient's physiology. This is not only due to the inhibition of an enzyme important in almost every organ and tissue in the body but also because of the general nature of the inhibitor as an analog of a proteinogenic amino acid as well as the initiation of cellular detoxification known to affect inflammatory pathways. In this review we provide a deeper insight into the physiological consequences of an IDO1 inhibiting therapy based on TRP related molecules. We discuss potential side and off-target effects that contribute to the interpretation of unexpected positive as well as negative results of ongoing or discontinued clinical studies while we also highlight the potential of these inhibitors independent of the IDO1 signaling pathway.
免疫肿瘤学仍然是癌症治疗中一个不断发展的领域。在这种治疗方法中，药物不是直接针对/攻击肿瘤，而是干扰免疫检查点，并针对或重新编程关键的代谢途径，这些途径对抗癌免疫防御至关重要。吲哚胺 2,3-双加氧酶 1（IDO1）和色氨酸（TRP）-犬尿氨酸途径被确定为癌症免疫逃逸的关键机制，其抑制作用具有很大的治疗潜力。特别是，大量的 IDO1 抑制色氨酸类似物已广泛应用于多项临床试验中。然而，这种治疗会对患者的生理机能产生多种影响。这不仅是因为该抑制剂抑制了一种在体内几乎每个器官和组织中都很重要的酶，还因为该抑制剂作为一种蛋白源氨基酸的类似物具有普遍性，以及众所周知的细胞解毒作用会影响炎症途径。在这篇综述中，我们基于 TRP 相关分子，深入了解 IDO1 抑制治疗的生理后果。我们讨论了可能的副作用和脱靶效应，这些副作用和脱靶效应有助于解释正在进行或已停止的临床研究中意外的阳性和阴性结果，同时我们还强调了这些抑制剂独立于 IDO1 信号通路的潜力。
