Indoleamine 2,3‐dioxygenase gene expression and kynurenine to tryptophan ratio correlation with nasopharyngeal carcinoma progression and survival

Abstract

Introduction Indoleamine 2,3‐dioxygenase (IDO) is an immunosuppressive tryptophan‐depleting enzyme expressed in nasopharyngeal carcinoma (NPC) tissue. However, IDO has not been reported in the peripheral blood of NPC patients. The aim of this study was to analyze, IDO1 and IDO2 messenger RNA (mRNA) expression, the kynurenine (Kyn) and tryptophan (Trp) plasma levels, their clinical values and their relationship with cytokine levels in NPC. Methods We evaluated IDO1 and IDO2 mRNA expression in peripheral blood mononuclear cells (PBMC) by quantitative real‐time PCR, plasma Trp and Kyn levels by HPLC, and cytokine levels by ELISA in 75 NPC patients and 51 healthy controls. Results Compared to controls, IDO1 mRNA expression was significantly upregulated and IDO2 mRNA expression was significantly downregulated in PBMC of patients. Also compared to controls, plasma Kyn levels and Kyn/Trp ratio were significantly higher in patients. At the time of diagnosis, the plasma Kyn/Trp ratio was associated with advanced cancer status and was an independent prognostic factor for worse disease‐specific survival. According to cancer stages, IDO1 mRNA expression was positively correlated with plasma Kyn/Trp ratio in patients with earlier stages (I–II–III) but negatively correlated in patients with the late‐stage cancer (IV). Tumor necrosis factor‐α, interleukin (IL)‐6 and IL‐10 levels were significantly higher in patients compared to controls. Moreover, and despite treatment, patients simultaneously carrying high plasma Kyn/Trp ratio and high plasma IL‐6 and IL‐10 levels at diagnosis died approximately 1 year after first diagnosis. Conclusion Measuring blood IDO mRNA expression and Kyn/Trp ratio at diagnosis could be a potential marker to evaluate NPC progression and predict survival outcome.

Comprehensive multi-omics analysis of tryptophan metabolism-related gene expression signature to predict prognosis in gastric cancer

“…Many studies have focused on the imbalances in tryptophan metabolism by targeting the KP, especially ryptophan-2,3-dioxygenase (TDO), indoleamine-2,3,-dioxygenase 1 (IDO1), and IDO2 ( Platten et al, 2019 ; Yao et al, 2021 ). It has been demonstrated that the tryptophan depletion by IDO1 and IDO2 was highly associated with cellular function and survival ( Zhai et al, 2018 ; Souissi et al, 2022 ). However, phase III clinical trials of IDO inhibitors against cancers were disappointing, although they did show promising outcome in early-stage cancer immunotherapy ( Günther et al, 2019 ; Chen et al, 2021 ).…”

Interleukin-6 and indoleamine-2,3-dioxygenase as potential adjuvant targets for Papillomavirus-related tumors immunotherapy

“…Interestingly, the STAT3/IL-6 axis is assumed to regulate the constitutive expression of IDO1 in tumor cells ( 16 ), leading to the hypothesis that this axis could regulate the high-level expression of IDO1 in the tumor microenvironment and adjacent tissues of HPV-related tumors ( 27 , 45 – 48 ), since both molecules are co-expressed in TC-1 cell mouse model or cervical cancer patients. Indeed, IL-6 and IDO have been linked to poor treatment outcomes, tumor recurrence, and aggressive tumor progression in breast cancer ( 49 ), nasopharyngeal carcinoma ( 50 ), and prostate cancer ( 51 ) patients. Therefore, the study of these two immunosuppressive molecules is important not only for HPV-related tumor, but also for other tumor types.…”