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

Baseline platelet production is dependent on thrombopoietin (TPO). TPO is constitutively produced and primarily regulated by receptor-mediated uptake by platelets. Inflammatory thrombocytosis is thought to be related to increased interleukin-6 (IL-6) levels. To address whether IL-6 might act through TPO to increase platelet counts, TPO was neutralized in vivo in C57BL/10 mice treated with IL-6, and hepatic TPO mRNA expression and TPO plasma levels were studied. Transcriptional regulation of TPO mRNA was studied in the hepatoblastoma cell line HepG2. Furthermore, TPO plasma levels were determined in IL-6-treated cancer patients. It is shown that IL-6-induced thrombocytosis in C57BL/10 mice is accompanied by enhanced hepatic TPO mRNA expression and elevated TPO plasma levels. Administration of IL-6 to cancer patients results in a corresponding increase in TPO plasma levels. IL-6 enhances TPO mRNA transcription in HepG2 cells. IL-6-induced thrombocytosis can be abrogated by neutralization of TPO, suggesting that IL-6 induces thrombocytosis through TPO. A novel pathway of TPO regulation by the inflammatory mediator IL-6 is proposed, indicating that the number of platelets by themselves might not be the sole determinant of circulating TPO levels and thus of thrombopoiesis. This regulatory pathway might be of relevance for the understanding of reactive thrombocytosis. IntroductionThrombocytosis can be classified into primary and secondary forms. Whereas primary thrombocytosis is observed in myeloproliferative syndromes, secondary or reactive thrombocytosis is noted in numerous clinical situations, 1 especially in association with inflammatory states of either infectious or noninfectious origin such as trauma and malignancy. 2,3 The extent to which mediators of the immune or hematopoietic system are involved in the regulation of the circulating platelet count in these conditions is insufficiently understood.Interleukin-6 (IL-6) plays a prominent role in inflammatory and neoplastic diseases. 4-6 Accordingly, mice deficient in IL-6 show a severely impaired acute-phase response. 7 Administration of IL-6 to humans has been associated with an increase in circulating platelet counts. [8][9][10][11][12][13][14] Furthermore, serum levels of IL-6 were significantly higher in patients with reactive thrombocytosis than in control patients. 15,16 Whether the thrombopoietic effect of IL-6 in vivo is caused by direct stimulation of hematopoietic progenitor cells or is indirectly mediated is unknown.Thrombopoietin (TPO), the ligand of the c-mpl proto-oncogene, is the primary regulator of proliferation and differentiation of megakaryocyte progenitors. [17][18][19][20][21][22][23] Mice rendered deficient in TPO or TPO receptor by gene targeting show severe thrombocytopenia, with platelet counts reduced by approximately 90%. 22,24 Treatment of mice, nonhuman primates, and humans with recombinant TPO or recombinant megakaryocyte growth and development factor, which constitutes a truncated, biologically active form of TPO, results in sig...