肿瘤细胞治疗研究
英文原题：A selective IDO1 inhibitor, KHK2455, improves efficacy of PD-L1 blockade by modulating both innate and adaptive immunity in a mouse melanoma model.
A selective IDO1 inhibitor, KHK2455, improves efficacy of PD-L1 blockade by modulating both innate and adaptive immunity in a mouse melanoma model.
吲哚胺2,3-双加氧酶1（IDO1）通过将色氨酸分解代谢为犬尿氨酸（Kyn）促进肿瘤进展。
吲哚胺2,3-双加氧酶1（IDO1）通过将色氨酸分解代谢为犬尿氨酸（Kyn）促进肿瘤进展。虽然选择性IDO1抑制剂KHK2455降低了小鼠肿瘤和血浆中的Kyn水平，但在小鼠黑色素瘤模型中并未发挥预期的抗肿瘤活性。然而，当与程序性死亡配体1（PD-L1）阻断联合使用时，KHK2455相比单独PD-L1阻断表现出增强的抗肿瘤效果。本研究探讨了IDO1抑制对肿瘤微环境的影响，以及IDO1抑制联合PD-L1阻断增强抗肿瘤效果的机制。PD-L1阻断上调了与适应性免疫相关的通路，包括1型和2型辅助性T细胞（Th1和Th2），而非固有免疫。另一方面，IDO1抑制上调了与固有免疫相关的基因和通路，如NK 细胞、中性粒细胞和巨噬细胞。此外，IDO1抑制与PD-L1阻断的联合比单独PD-L1阻断更多地上调了适应性和固有免疫应答。这些发现阐明了两种疗法对免疫系统的不同影响，并为未来靶向IDO1的治疗策略提供了有价值的见解。
Indoleamine 2,3-dioxygenase 1 (IDO1) facilitates tumor progression by catabolizing tryptophan into kynurenine (Kyn). While KHK2455, a selective IDO1 inhibitor, reduced Kyn levels in mouse tumors and plasma, it did not exert the expected antitumor activity in a mouse melanoma model. However, when combined with programmed death-ligand 1 (PD-L1) blockade, KHK2455 demonstrated enhanced antitumor effects compared with PD-L1 blockade alone. This study investigated the effects of IDO1 inhibition on the tumor microenvironment and mechanisms underlying the enhanced antitumor effects of combining IDO1 inhibition with PD-L1 blockade. PD-L1 blockade upregulated the pathways related to adaptive immunity including T-helper cells type 1 and 2 (Th1 and Th2) rather than innate immunity. On the other hand, IDO1 inhibition upregulated genes and pathways associated with innate immunity, such as natural killer cells, neutrophils, and macrophages. Furthermore, the combination of IDO1 inhibition and PD-L1 blockade upregulated both adaptive and innate responses more than PD-L1 blockade alone. These findings elucidate the differential effects of the two therapies on the immune system and provide valuable insights for future treatment strategies targeting IDO1.
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