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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Stress or heat shock proteins (hsp) are a family of approximately two dozen proteins with a high degree of amino acid sequence homology between different species, ranging from prokaryotes to humans, and are representative of a generalized response to environmental and metabolic stressors. Our previous studies showed increased expression of human hsp6O on endothelial cells of arterial intima with atherosclerotic lesions, and elevated levels of serum antibodies (Ab) against hsp65/60 in subjects with carotid atherosclerosis. To investigate the possible involvement of anti-hsp65/60 Ab in endothelial injury, specific hsp-Ab were isolated from human high titer sera by affinity chromatography and probed on heat-shocked human umbilical vein endothelial cells. Purified human anti-hsp65/60 Ab reacted specifically with mycobacterial hsp65, human hsp60, and a 60-kD protein band of heat-shocked endothelial cells. (5, 6). As a matter of fact, immunization of rabbits with recombinant mycobacterial hsp65 induced the development of atherosclerotic lesions at characteristic predilection sites known to be subject to increased hemodynamic stress, such as the aortic and the branching of large vessels (7). A previous epidemiological study (8) from our laboratory had demonstrated that serum antibodies to mycobacterial hsp65, which is a homologue of human hsp6O, were significantly increased in clinically healthy subjects with sonographically demonstrable carotid atherosclerosis compared to those without lesions. This increased antibody level was independent of other established risk factors, such as hyperlipidemia, smoking, hypertension, diabetes mellitus, and obesity, thus providing evidence for a strong correlation of hsp65 antibodies with carotid atherosclerosis. These serum antibodies cross-reacted with recombinant human hsp6O homologue, and also with homogenates of atherosclerotic lesions both showing a 60-kD protein band on Western blots (9). Double-immunofluorescence labeling of atherosclerotic lesions with human anti-hsp65 sera and cell marker-specific antibodies demonstrated expression of hsp60 by endothelial cells, as well as by macrophages and smooth muscle cells therein. These findings indicated the existence of serum antibodies reacting not only with mycobacterial hsp65 but also with mammalian hsp60, expressed as an autologous cellular component (6,9).Based on these observations we next addressed the question whether human anti-hsp65/60 antibody (Ab) from high titer sera could react with surface proteins, e.g., hsp60 on stressed endothelial cells, and whether these antibodies could mediate 1. Abbreviations used in this paper: ADCC, antibody-dependent cellular cytotoxicity; hsp, heat shock protein.Schett, Xu, Amberger, Van der Zee, Recheis, Willeit, and Wick 2569 J. Clin. Invest.

Methylation of the RAR-beta2 gene may be an initial step in breast carcinogenesis; treatment of cancer patients with demethylating agents followed by retinoic acid may offer a new therapeutic modality.