Purpose: The pathologic interactions between tumor and host immune cells within the tumor microenvironment create an immunosuppressive network that promotes tumor growth and protects the tumor from immune attack. In this study, we examined the contribution of the immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) on this phenomenon. Experimental Design: Expression of IDO was analyzed in colorectal cancer cell lines by reverse transcription-PCR and functional enzyme activity was assessed by high-pressure liquid chromatography. Semiquantitative immunohistochemistry was used to evaluate IDO expression in the tissue samples of 143 patients with colorectal carcinoma, and was then correlated with the number of tumor-infiltrating T cells and clinical variables. Results: In vitro IDO expression and functional enzyme activity in colorectal cancer cells was found to be strictly dependent on IFN-g stimulation. Immunohistochemical scores revealed IDOhigh expression in 56 of143 (39.2%) tumor specimens, whereas 87 of143 (60.8%) cases showed low IDO expression levels. IDO-high expression was associated with a significant reduction of CD3+ infiltratingT cells (46.02 F 7.25) as compared with tissue samples expressing low IDO (19.42 F 2.50; P = 0.0003). Furthermore, IDO-high immunoreactivity significantly correlated with the frequency of liver metastases (P = 0.003). Kaplan-Meier analysis showed the crossing of survival curves at 45 months. By multivariate Cox's analysis, IDO-high expression emerged as an independent prognostic variable (<45 months, P = 0.006; >45 months, P = 0.04).Conclusion: IDO-high expression by colorectal tumor cells enables certain cancer subsets to initially avoid immune attack and defeat the invasion of Tcells via local tryptophan depletion and the production of proapoptotic tryptophan catabolites. Thus, IDO significantly contributes to disease progression and overall survival in patients with colorectal cancer.Colorectal cancer is the most common gastrointestinal malignancy and one of the leading causes of cancer-related deaths worldwide (1). Five-year overall survival rates range from 90% for stage I to 75% and 50% for stage II and III

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Background: Indoleamine (2,3)-dioxygenase (IDO) catalyses the initial, rate-limiting step in the degradation of the essential amino acid tryptophan. Via tryptophan deprivation, IDO activity suppresses T cell proliferation and differentiation and is thought to be a fundamental immune escape mechanism for tumor cells. Objective and Methods: To investigate the potential role of tryptophan degradation as a prognostic marker, serum tryptophan and kynurenine concentrations and the kynurenine-to-tryptophan ratio (kyn/trp) in 87 patients with malignant melanoma were compared to the course of the disease and to concentrations of the immune activation marker neopterin. Results: Compared to 49 healthy volunteers, the melanoma patients presented with lower tryptophan levels due to accelerated degradation. This was especially true for the subgroups of patients with distant metastases (p = 0.01), though not in patients with lymph node metastases or in patients who had not yet progressed. There existed a positive correlation between kyn/trp and neopterin concentrations (r_s = 0.587, p <0.001). In patients who died due to dissemination of the tumor, median tryptophan concentrations were significantly decreased (p = 0.006) and kyn/trp (p = 0.03) and neopterin concentrations (p = 0.002) were higher compared to survivors. In addition, lower tryptophan concentrations as well as higher kyn/trp and neopterin concentrations predicted a shorter survival. Conclusion: Decreased serum tryptophan concentrations and elevated serum neopterin levels can be used as predictive markers for the future course in melanoma patients. Moreover, our data support previous speculations that a higher degree of IDO expression could play a crucial role for tumor progression.