Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells.

Abstract

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

Indoleamine 2,3-dioxygenase is a novel prognostic indicator for endometrial cancer

“…Surprisingly, of the 43 patients with no or weak IDO expression, only one patient developed disease progression/recurrence, whereas 13 out of the 37 patients with high IDO expression recurred. Consistently, three recent reports showed the correlation between the high IDO expression and poor patient prognosis in ovarian cancer, lung cancer, and colorectal cancer (Astigiano et al, 2005;Okamoto et al, 2005;Brandacher et al, 2006), although they only analysed the OS. More importantly, our analysis, focusing on the cases with early-staged disease (FIGO I/II), showed that the patients with no or weak expression of IDO achieved 100% PFS, whereas five out of 24 patients with the high IDO expression developed recurrence (PFS ¼ 75%), and three out of the five recurred cases were FIGO stage 1B.…”

“…Thus, the correlation of the high IDO expression with disease progression and the impaired patient survival shown by the present study may be attributable to the immune suppression by the tumour-mediated IDO activity. This may be supported by one recent report showing the association of high IDO expression with a reduction of CD3 þ lymphocytes in colorectal cancer (Brandacher et al, 2006). Another possible mechanism by which IDO contributes to cancer progression was proposed by Muller et al (2005), who demonstrated the involvement of IDO in a chemoresistance in cancer.…”

“…The high IDO expression was significantly correlated with the advanced stage, the depth of myometrial invasion, the presence of lymphvascular space involvement, and lymph node metastasis, but not with the histological grade. Consistently, Brandacher et al (2006) showed that the high IDO expression in colorectal cancer was correlated with the disease stage and liver metastasis, but not with tumour differentiation. These results suggest that the high IDO The present data clearly demonstrated that the patients with high IDO expression had an impaired clinical outcome by analysing the rates of both OS and PFS.…”

“…Based on the above findings, considerable attention is now being paid to the functional role of IDO in the progression of human cancer and its therapeutic potential as a new prognostic marker or a molecular target. However, there have been few studies on IDO expression in a large number of human tumour samples (Brandacher et al, 2006), and its prognostic significance has not yet been well studied.…”

IDO expression in the brain: a double-edged sword

“…In ovarian and colorectal cancer, IDO expression within the tumors correlates to malignancy [53]. In support of this concept, colorectal tumors exhibiting a high IDO activity have a significantly reduced number of CD3 + infiltrating T cells and show an increased frequency of metastases [54]. Thus, determining IDO expression in tumors may be used for clinical prognostic in the future.…”