Fig. 4. Selective AHR inhibition reverses IDO/TDO-mediated tumor progression and improves the efficacy of PD-1 blockade.

a Top left: scheme figure with experimental approach of targeting multiple steps of Trp-catabolic pathway. Top right: therapy regimen (PO, QD). Bottom: tumor progression of orthotopically injected B16^WT, B16^IDO and B16^TDO tumors in mice treated with vehicle or inhibitors (Epacadostat/IDO inhibitor 300 mg/kg/d, 680C91/TDO inhibitor 20 mg/kg/d, CH-223191/AHR inhibitor 50 mg/kg/d). (n = 5 mice per group for two independent experiments). b FACS analysis of MHCII expression (n = 4 per group, n = 5 B16^IDO vehicle). c Quantification of frequency and representative plots of intratumor Tregs (CD4⁺FoxP3⁺CD25⁺/% of CD45⁺) and d, quantification of frequency and representative plots of Ki67⁺PD-1⁺ CD8⁺ T cells from B16^WT and B16^IDO-bearing mice treated with vehicle or AHR inhibitor (CH-223191) (n = 4 per group). e Top: therapy regimen. bottom: mean tumor size and overall survival of B16^IDO and B16^TDO tumor-bearing mice treated with AHR inhibitor (CH-223191), anti-PD-1 alone or in combination with AHR inhibitor (combo) (n = 5 B16^TDO and n = 10 B16^IDO). f Mean tumor size of B16^IDO and CT26 and g, overall survival of B16^IDO tumor-bearing mice treated with the optimized AHR inhibitor (KYN-101), anti-PD-1 alone or in combination with AHR inhibitor (combo) (n = 10 mice per group). Results are representative of two independent experiments. Data represented as mean values ± SEM. Two-tailed Student’s t test was used when only two groups were compared and log-rank (Mantel–Cox) test was used for survival comparison. P value: *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.