Impact of Indoleamine 2,3-Dioxygenase Enzyme Activity in Neuroendocrine Tumors

Abstract

Introduction: Indoleamine 2,3-dioxygenase (IDO) converts L-tryptophan (T) to L-kynurenine (K) resulting in an immunosuppressive microenvironment. The aim of the current study was to evaluate in patients with neuroendocrine tumor (NET) (1) T and K concentrations; (2) correlation with clinical outcome; (3) relationship between IDO activity and inflammatory cytokines.

Methods: A cross-sectional study was performed to investigate the IDO pathway in patients in follow-up for NET. Clinicopathological features, serum levels of K and T through liquid chromatography, and serum assay of cytokines (IL-6, IL-10, IL-17A, IL-22, IL-23, TNF-α) through MAGPIX were evaluated.

Results: Seventy-eight NET patients were enrolled (66 lung, 12 pancreatic): 69.2% were in postoperative remission, 14.1% in stable disease, and 16.7% in disease progression. T was significantly lower in patients older than 65 years (p = 0.003). K and T were significantly lower in patients with progression (p = 0.03, p = 0.004, respectively). T was an independent predictor factor of progression in multivariable analysis (p = 0.041). A cutoff of 7.74 μg/mL significantly differentiates patients with progression and those with stable disease. IL-6 and IL-10 were significantly associated with tumor progression in univariate analysis (p = 0.005, p = 0.001, respectively) but not in the multivariable analysis. A statistically significant negative correlation was found between T and IL-10 (r = -0.366, p value = 0.04).

Conclusion: The K/T pathway may play a role as a potential predictor of tumor progression in NET. These findings need to be validated in large prospective studies investigating its metabolites as both prognostic and predictive factors for treatment response.

Keywords: Cytokines; Immunotherapy; Indoleamine 2,3-dioxygenase; Kynurenine; Neuroendocrine tumors; Tryptophan.

Fig. 1.

L-kynurenine, L-tryptophan, and K/T ratio in NET patients with stable and progressive disease. The mean values of L-kynurenine (K), L-tryptophan (T), and their ratio (K/T) in patients with neuroendocrine tumors (NETs) accompanied by SDs. The data correspond to the last three rows of Table 3. A key finding illustrated by the figure is that T and K levels were significantly lower in patients with disease progression compared to those with stable disease (6.76 ± 1.77 vs. 8.55 ± 2.23, p value 0.004; 0.14 ± 0.06 vs. 0.19 ± 0.07, p value 0.03, respectively). This suggests a potential role of tryptophan depletion in disease progression, which could be explored as a prognostic indicator in NET.