The expression of the immunomodulating enzyme indoleamine-2,3-dioxygenase (IDO) suppresses T-lymphocyte function, thus correlating with poor survival in a variety of cancer patients. IDO degrades the essential amino acid tryptophan leading to immunosuppressive kynurenines production. In the present study, concentrations of tryptophan, 3-hydroxykynurenine, and kynurenine were measured in pre-treatment serum samples of 251 cervical cancer patients by a mass-spectrometric method (XLC-MS/MS) and IDO activity determined by the kynurenine/tryptophan (Kyn/Trp) ratio. A low concentration of tryptophan was found to be significantly associated with tumors greater than 4 cm and lymph node metastatic spread. Furthermore, significant positive correlations were found between high concentrations of the tryptophan metabolites kynurenine and 3-hydroxykynurenine and advanced disease stage (FIGO >IIA) and lymph node metastases. High levels of kynurenine were further associated with parametrial invasion and tumor size. A high Kyn/Trp ratio was related to lymph node metastasis, FIGO stage, tumor size, parametrial invasion and poor disease-specific survival. These results suggest that IDO activation is linked to poor clinicopathological parameters and worse survival in cervical cancer, warranting the use of IDO inhibitors in future clinical trials.
Keywords: FIGO, International Federation of Gynaecologists and Obstetricians; Gy, Gray; HPV, human papillomavirus; IDO; IDO, indoleamine-2,3-dioxygenase; IFNγ, interferon γ; Kyn/Trp ratio; Kyn/Trp ratio, kynurenine/tryptophan ratio; M0, no metastasis; NK, natural killer; SCC, squamous cell carcinoma; TDO. tryptophan-2,3-dioxygenase; TLR: toll-like receptor; Tregs, regulatory T cells; XLC-MS/MS- extraction: liquid chromatographic tandem mass spectrometry; cervical cancer; kynurenine; tryptophan.