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

Abstract

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-γ (IFN-γ), 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 $G3+$ (greater than or equal to Grade 3) RILT. Preradiation IDO1 activity was significantly higher in patients who developed $G3$  + RILT than in non $G3$  + RILT patients. ( $P=0.029$ , AUC = 0.70). Univariate and multivariate analyses showed that high IDO1 activity was independently associated with the risk of $G3$  + RILT ( $P=0.034$ ). A predictive model combining both IDO1 activity and FEV1 was established for severe RILT and displayed a moderate predictive value (AUC = 0.83, $P<0.001$ ). The incidence of $G3$  + 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 ( $P=0.021$ ), though no significant differences among the three time points were observed ( $P=0.070$ ). 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.