A selective IDO1 inhibitor, KHK2455, improves efficacy of PD-L1 blockade by modulating both innate and adaptive immunity in a mouse melanoma model.

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.