Immunobiochemical pathways of neopterin formation and tryptophan breakdown via indoleamine 2,3-dioxygenase correlate with circulating tumor cells in ovarian cancer patients- A study of the OVCAD consortium.

Objective: Circulating tumor cells (CTCs) may represent a chronic stimulus for the immune system. In the present study we investigated the potential association of CTCs, the immune activation marker neopterin, and the ratio of kynurenine to tryptophan (Kyn/Trp) as a measure for tryptophan breakdown.

Methods: Neopterin, tryptophan and kynurenine levels were measured in plasma samples from patients with benign gynecological diseases (n=65) and with primary advanced epithelial ovarian cancer (EOC) at diagnosis (n=216) and six months after adjuvant platinum-based chemotherapy (n=45) by an enzyme-linked immunosorbent assay and high performance liquid chromatography. The presence of CTCs had been assessed in a previous study by qPCR-based analysis of CTC-related transcripts in the blood. The respective plasma levels in EOC and benign samples were compared using a two-tailed Chi or Fisher's exact test. The associations of the analytes and Kyn/Trp with clinicopathological parameters, platinum-sensitivity, and the presence of CTC-related transcripts were assessed using a two-sided t-test. Associations with patient outcome were evaluated using Cox regression analysis.

Results: In EOC, elevated Kyn/Trp and neopterin levels were associated with advanced disease, peritoneal carcinomatosis, ascites, sub-optimal debulking, poor response to therapy and worse outcome. Likewise, neopterin and Kyn/Trp were elevated in CTC-positive patients, both at diagnosis and at follow-up in platinum-sensitive disease.

Conclusions: We observed concomitant alterations of CTCs and immune system related biomarkers suggesting that immune responses along with increase of neopterin and Kyn/Trp concentrations are not necessarily only located at the site of the tumor, but may also go on in the circulation.