High Expression of Kynurenine Pathway Markers in Glioblastoma: Prognostic Relevance

Abstract

Purpose Glioblastoma (GBM) continues to exhibit a discouraging survival rate despite massive efforts to improve therapeutic outcomes. Among other factors, an immunosuppressive microenvironment contributes to this treatment resistance. Notably, the kynurenine pathway (KP) has emerged as a potent regulator of the tumour immune environment in glioblastoma. Our study aimed to investigate the influence of the kynurenine pathway on the survival of newly diagnosed GBM patients. Methods GBM tissues of 108 patients were assessed for the expression of key kynurenine pathway markers by immunohistochemistry: tryptophan 2,3-dioxygenase (TDO2), indoleamine 2,3-dioxygenase (IDO1/2) and the aryl hydrocarbon receptor (AhR). For each individual patient, three tumour cores were used and the expression levels of KP markers were scored by using QuPath. Kaplan-Meier and stepwise multivariate Cox-Regression analyses were used to assess the impact of these KP markers on survival. Results Patients with high concomitant expression of TDO2, IDO1/2, and AhR had a shorter survival than patients with low KP marker expression. This remained significant even in multivariate analyses (IDO1 HR = 3.393, 95%CI: 1.707–6.748, P < .001; IDO2 HR = 2.775, 95%CI: 1.504–5.119, P = .001; TDO2: HR = 1.891, 95%CI: 1.105–3.236, P = .020; AhR HR = 1.902, 95%CI: 1.160–3.119, P = .011). Conclusion High expression of concomitant KP markers is of significant negative independent prognostic value for GBM patient survival probably due to their immunosuppressive properties. KP markers might be used for patient stratification for treatment purposes with respect to potential future immunomodulating trials.