Kynurenine/Tryptophan Ratio as a Potential Blood-Based Biomarker in Non-Small Cell Lung Cancer

Abstract

The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) degrade tryptophan (Trp) into kynurenine (Kyn) at the initial step of an enzymatic pathway affecting T cell proliferation. IDO1 is highly expressed in various cancer types and associated with poor prognosis. Nevertheless, the serum Kyn/Trp concentration ratio has been suggested as a marker of cancer-associated immune suppression. We measured Kyn and Trp in blood samples of a wide cohort of non-small-cell lung cancer (NSCLC) patients, before they underwent surgery, and analyzed possible correlations of the Kyn/Trp ratio with either IDO1 expression or clinical–pathological parameters. Low Kyn/Trp significantly correlated with low IDO1 expression and never-smoker patients; while high Kyn/Trp was significantly associated with older (≥68 years) patients, advanced tumor stage, and squamous cell carcinoma (Sqcc), rather than the adenocarcinoma (Adc) histotype. Moreover, high Kyn/Trp was associated, among the Adc group, with higher tumor stages (II and III), and, among the Sqcc group, with a high density of tumor-infiltrating lymphocytes. A trend correlating the high Kyn/Trp ratio with the probability of recurrences from NSCLC was also found. In conclusion, high serum Kyn/Trp ratio, associated with clinical and histopathological parameters, may serve as a serum biomarker to optimize risk stratification and therapy of NSCLC patients.

Predicting dynamic response to neoadjuvant chemotherapy in breast cancer: a novel metabolomics approach

“…Specifically postsurgery, a significant decrease in Trp plasmatic concentrations was observed, as previously reported in serum and plasma of BC patients [58–60]. In this regard, Trp catabolism dysregulation is known to indirectly contribute to cancer progression by the kynurenine (Kyn) pathway [61–63], although no associations with response or sensitivity to chemotherapy were observed in previous studies, which coincides with our observations [22,64]. In this line, further investigating the metabolome alteration related to treatment response is still needed to better understand the behavior of the LB and HER2+ molecular subtypes in response to NACT.…”

Clinical Relevance of Serum Kyn/Trp Ratio and Basal and IFNγ-Upregulated IDO1 Expression in Peripheral Monocytes in Early Stage Melanoma

“…PFS rates in stage I-III patients with a high Kyn/ Trp ratio was lower than in patients with low Kyn/Trp ratio (55 months versus 99 months), but Kyn/Trp was not independent from disease stage in multivariate analysis. An elevated Kyn/Trp ratio has been previously linked to larger tumor size and more advanced disease stages (32)(33)(34).…”

The immunosuppressive role of indoleamine 2, 3-dioxygenase in glioblastoma: mechanism of action and immunotherapeutic strategies

“…Numerous studies have shown that the higher relative concentration of Kyn compared with Trp, and thus the Kyn/Trp ratio, is a promising surveillance biomarker for predicting the clinicopathologic status of tumors to monitor cancer invasion and progression [ 97 , 99 ]. Considering the recent findings of enhanced Trp degradation, and the active transport of Trp products such as Kyn across the blood–brain barrier (BBB), as well as the immunomodulatory effects of IDO1-mediated Trp degradation, analysis of the Kyn/Trp ratio in the patient's peripheral blood has been considered as a potential marker of cancer progression and to optimize risk stratification and therapy for GBM patients [ 100 , 101 ]. Moreover, the activity of IDO in non-tumor cells, such as DCs in peripheral blood, has been shown to contribute to higher serum Kyn/Trp levels[ 102 ].…”

“…Interestingly, the Kyn/Trp index in the serum of GBM patients appears to be an accurate predictor of enrollment in immunotherapeutic treatments [ 101 ]. In GBM patients treated with surgery and immunotherapy, both prognostic and predictive values of the serum Kyn/Trp ratio have been proposed [ 100 , 101 ]. To date, several techniques have been developed to quantify Trp and seven of its KP metabolites (KYN, 3-HK, 3-HAA, KYNA, XANA, QUIN, and PA) in biological samples, including high-performance liquid chromatography (HPLC), gas chromatography (GC), liquid chromatography (LC), mass spectrometry (MS), and high-voltage paper electrophoresis (HVPE) [ 104 ].…”