Accumulation of an Endogenous Tryptophan-Derived Metabolite in Colorectal and Breast Cancers

Abstract

Tumor immune escape mechanisms are being regarded as suitable targets for tumor therapy. Among these, tryptophan catabolism plays a central role in creating an immunosuppressive environment, leading to tolerance to potentially immunogenic tumor antigens. Tryptophan catabolism is initiated by either indoleamine 2,3-dioxygenase (IDO-1/-2) or tryptophan 2,3-dioxygenase 2 (TDO2), resulting in biostatic tryptophan starvation and l-kynurenine production, which participates in shaping the dynamic relationship of the host’s immune system with tumor cells. Current immunotherapy strategies include blockade of IDO-1/-2 or TDO2, to restore efficient antitumor responses. Patients who might benefit from this approach are currently identified based on expression analyses of IDO-1/-2 or TDO2 in tumor tissue and/or enzymatic activity assessed by kynurenine/tryptophan ratios in the serum. We developed a monoclonal antibody targeting l-kynurenine as an in situ biomarker of IDO-1/-2 or TDO2 activity. Using Tissue Micro Array technology and immunostaining, colorectal and breast cancer patients were phenotyped based on l-kynurenine production. In colorectal cancer l-kynurenine was not unequivocally associated with IDO-1 expression, suggesting that the mere expression of tryptophan catabolic enzymes is not sufficiently informative for optimal immunotherapy.

Therapeutic targeting of inflammation and tryptophan metabolism in colon and gastrointestinal cancer

“…147 Positivity was noted in the neoplastic epithelium of 20% of 69 CRC samples and was not detected in normal colon epithelial cells. Positivity of IDO1 and kynurenine staining overlapped in only 42% of cases.…”

TDO2 Overexpression Is Associated with Cancer Stem Cells and Poor Prognosis in Esophageal Squamous Cell Carcinoma

“…Overexpression of TDO2 promoted tumor cell survival and was correlated with tumor grade and poor prognosis in triple negative breast cancer [18] and in brain tumors [19]. Furthermore, overexpression of TDO2 has been reported in human colorectal cancer and leiomyosarcoma [20,21]. However, the expression and biological significance of TDO2 in esophageal cancer have not been investigated.…”

The Kynurenine Pathway: A Primary Resistance Mechanism in Patients with Glioblastoma

“…TDo has been found to have a role in numerous neurological diseases, including Alzheimer's disease, parkinson's disease and autism, and suppression of TDo appears to reduce neurodegeneration (111)(112)(113)(114). increased TDo activity is associated with cancer growth (115)(116)(117), as well as with increased tumor grade and decreased survival in triplenegative breast cancer cells (118).…”