Impact of indoleamine 2,3-dioxygenase enzyme activity in neuroendocrine tumors.

Introduction: Indoleamine-2,3-dioxygenase (IDO) converts L-tryptophan (T) to L-kynurenine (K) resulting in an immunosuppressive microenvironment. Aim of the current study is 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. Clinico-pathological 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: 78 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 cut-off 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 on univariate analysis (p=0.005, p=0.001, respectively), but not at the multivariable. 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.