IDO1 Activity Predicts Lung Toxicity in Patients with Unresectable Stage III NSCLC and Chemoradiotherapy.

Objectives: Indoleamine 2,3-dioxygenase 1 (IDO1) acts as the key rate-limiting enzyme that converts tryptophan (Trp) to kynurenine (Kyn). Its activity was primarily induced by interferon- (IFN-), which was reported to play a role in the development of acute radiation-induced pneumonitis. In this study, we aimed to investigate the correlation between IDO1 activity and radiation-induced lung toxicity (RILT) in stage III nonsmall cell lung cancer (NSCLC) patients who were treated with chemoradiotherapy (CRT).

Materials And Methods: Systemic IDO1 activity was reflected by Kyn : Trp ratio. Plasma levels of Kyn and Trp in 113 stage III NSCLC patients were measured by high-performance liquid chromatography (HPLC) before the initiation of radiotherapy. Dynamic change of IDO1 activity was followed in 23 patients before, during, and after radiotherapy. We also used RNA sequencing (RNA-seq) data from the Cancer Genome Atlas Program (TCGA) database and performed gene set enrichment analysis (GSEA) to explore how IDO1 was involved in the development of RILT.

Results: 9.7% (11/113) of the whole group developed 3+ (greater than or equal to Grade 3) RILT. Preradiation IDO1 activity was significantly higher in patients who developed 3 + RILT than in non3 + RILT patients. ( = 0.029, AUC = 0.70). Univariate and multivariate analyses showed that high IDO1 activity was independently associated with the risk of 3 + RILT ( = 0.034). A predictive model combining both IDO1 activity and FEV1 was established for severe RILT and displayed a moderate predictive value (AUC = 0.83, < 0.001). The incidence of 3 + RILT was 2.6% (1/38) in patients with an IDO activity ≤0.069 and FEV1 > 59.4%, and 50.0% (6/12) in those with an IDO activity >0.069 and FEV1 ≤ 59.4%. Of 23 patients with dynamic tracking, the IDO1 activity of postradiation was significantly lower than midradiation ( = 0.021), though no significant differences among the three time points were observed ( = 0.070). Bioinformatic analysis using RNA-seq data from 1014 NSCLC patients revealed that IDO mainly functioned in the inflammatory response instead of the late fibrosis process in NSCLC patients.

Conclusion: High baseline IDO1 activity combined with unfavorable baseline FEV1 was predictive of severe RILT in unresectable stage III NSCLC patients. IDO1 might play a role in the acute inflammatory response. Finding effective interventions to alleviate RILT using IDO inhibitors is warranted in the future.