Increased Activity of the Immunoregulatory Enzyme Indoleamine-2,3-Dioxygenase (IDO) with Consecutive Tryptophan Depletion Predicts Death in Patients with Neuroendocrine Neoplasia.

Pschowski, Rene; Pape, Ulrich-Frank; Fusch, Gerhard; Fischer, Christian; Jann, Henning; Baur, Alexander; Arsenic, Ruza; Wiedenmann, Bertram; von Haehling, Stephan; Pavel, Marianne; Schefold, Joerg C. (2017). Increased Activity of the Immunoregulatory Enzyme Indoleamine-2,3-Dioxygenase (IDO) with Consecutive Tryptophan Depletion Predicts Death in Patients with Neuroendocrine Neoplasia. Neuroendocrinology, 104(2), pp. 135-144. Karger 10.1159/000445191

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BACKGROUND/AIMS

Data from a considerable number of malignancies demonstrate that depletion of the essential amino acid tryptophan via induction of the immuno-regulatory enzyme Indoleamine-2,3-dioxygenase (IDO) serves as an important tumour escape strategy and is of prognostic importance. Here we investigate the predictive value of the activity of IDO as well as levels of tryptophan and respective downstream catabolites in a large cohort of patients with neuroendocrine neoplasia (NEN).

METHODS

142 consecutive Caucasian patients (62 male, aged 60.3 ± 11.9 years) with histologically confirmed NEN were systematically analysed in a retrospective blinded endpoint analysis. Patients were followed up for a mean period of about 3.9 ± 1.9 years. Clinical outcome, levels of established biomarkers, and tryptophan degradation markers (assessed using tandem mass spectrometry) including estimated IDO-activity were recorded. Cox-proportional hazards regression models were performed for the assessment of prognostic power.

RESULTS

We found that baseline tryptophan levels were significantly lower and IDO-activity was significantly increased in non-survivors. The risk for death inclined stepwise and was highest in patients in the upper tertile of IDO-activity. Cox-proportional regression models identified IDO-activity as an independent predictor for death.

CONCLUSIONS

In this retrospective analysis, we observed that baseline activity of the immunoregulatory enzyme IDO was significantly increased in non-survivors. IDO-activity was identified as an independent predictor for death in this cohort of NEN patients. Whether IDO-activity or tryptophan depletion serves to guide future therapeutic interventions in NEN remains to be established.

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