Pan-cancer analysis of IDO1 transcriptome expression and its impact on outcome in patients treated with immune checkpoint inhibitors.
Authors: Fujiwara Yu , Kato Shumei , Nishizaki Daisuke , Miyashita Hirotaka , Lee Suzanna , Nesline Mary K , Conroy Jeffrey M. , DePietro Paul , Pabla Sarabjot , Lippman Scott Michael , Kurzrock Razelle 
Published: June 2023

2614

Background: The immunosuppressive tumor microenvironment (TME) is a major component of resistance to immune checkpoint inhibitors (ICIs). Tryptophan catabolism is recognized as a metabolic pathway leading to immunosuppression and indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme catabolizing tryptophan to kynurenine, has been investigated as a potential target. Analyzing the association of IDO1 and immune molecules in the TME could better elucidate the role of IDO1 as an immunotherapeutic strategy. Thus, we performed pan-cancer transcriptome analysis of IDO1 according to cancer types and immune molecules in the TME and evaluated survival outcomes in patients treated with ICIs based on IDO1 expression levels. Methods: Comprehensive transcriptome analysis of IDO1 and selected immune molecules in 514 patients with advanced solid tumors at the Moores Cancer Center at the University of California San Diego was performed. The rate of “High” (75-100 percentile), “Intermediate” (25-74), and “Low” (0-24) IDO1 RNA expression in each cancer type was calculated (rank compared to 735 controls). Univariate and multivariate analyses of the odds ratio (OR) for high IDO1 expression based on factors such as immune checkpoints, cancer types, microsatellite instability (MSI), and tumor mutational burden (TMB) were conducted. Additionally, progression-free survival (PFS) and overall survival (OS) from the time of ICI therapy based on IDO1 expression was compared by the Kaplan-Meier method. Multivariate analysis of survival outcomes was performed using the Cox proportional hazards model. Results: Overall, 91 of 514 patients (17.7%) were classified into “High”, 228 (44.4%) into “Intermediate”, and 195 (37.9%) into “Low” IDO1 RNA expression. High IDO1 expression was seen in uterine (54.2%), ovarian (37.2%), and lung cancer (25.0%). In multivariate analysis, high STAT1 and CD40 expression, ovarian cancer, and uterine cancer were correlated with high IDO1 expression. In patients treated with ICIs (N = 217), “High” IDO1 expression (N = 49) was associated with better PFS (HR = 0.57, 95%CI: 0.40-0.83, p = 0.003) and OS (HR = 0.52, 95%CI: 0.47-0.83, p = 0.006) than “Intermediate/Low” IDO1 expression (N = 168). Multivariate analysis incorporating age, sex, IDO1, PD-1, PD-L1, PD-L2, CTLA-4, LAG3, cancer types, TMB, and MSI revealed that IDO1 (HR = 0.28, 95%CI: 0.11-0.69, p = 0.006) and PD-1 (HR = 0.24, 95%CI: 0.09-0.65, p = 0.005) are independent predictive factors for longer OS. Conclusions: IDO1 RNA levels are high in >25% of uterine, ovarian, and lung cancers but differ from patient to patient between and within tumor types. High IDO1 levels correspond with longer PFS and OS from start of ICI therapy. These results suggest the importance of patient selection through pan-cancer molecular analysis and the potential role of IDO1 as a predictive marker for ICI therapy.