Non-tumor cell IDO1 non-enzymatically decreases

radiation + PD-1 mAb treatment efficacy in older adults with glioblastoma

To understand the role of indoleamine 2,3 dioxygenase 1 (IDO1) in the age-dependent immunotherapeutic effect, we compared 20-26 month-old C57BL/6 background mice that were IDO1-T2A-GFP [(WT); n=16], IDO1 enzyme null [H350A; (n=16)], IDO1KO (n=4), Ido1^fl/fl (n=14), Lysm-Cre⁺→Ido1^fl/fl  (n=20), CD11c-Cre⁺→Ido1^fl/fl (n=23), Tie2-Cre⁺→Ido1^fl/fl (n=14) treated with RT + PD-1 mAb. Mice were intracranially engrafted (ic.) with GL261 cells followed by RT + PD-1 mAb beginning at 14-days post-ic. IDO1 WT and IDO1 enzyme null (H350A) mice had a survival rate of 12.5% and 18.75% at 90-days post ic., respectively, which was significantly decreased as compared to IDO1KO mice with a 75% survival rate (p<0.05). Tie2-Cre⁺→Ido1^fl/fl mice, CD11c-Cre⁺→Ido1^fl/fl, and Lysm-Cre⁺→Ido1^fl/fl mice had a 100%, 96%, and 70% survival rate at 90-days post ic., respectively, as compared to uncrossed Ido1^fl/fl mice with a 42% survival rate (p<0.05). Significantly reduced kynurenine (KYN) levels were found in IDO1 enzyme null (H350A) and IDO1KO mice as compared to WT mice (p<0.001). Unexpectedly, KYN levels were also decreased in Tie2-Cre⁺→Ido1^fl/fl but not in CD11c-Cre⁺→Ido1^fl/fl, Lysm-Cre⁺→Ido1^fl/fl or Ido1^fl/fl mice (p<0.05). Tryptophan (TRP) levels did not change between mouse groups. These data support the hypothesis that non-tumor cell IDO1 reduces immunotherapeutic efficacy in older adults with GBM through a TRP-KYN pathway-independent mechanism.