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Expression of Indoleamine 2,3-Dioxygenase in Tumor Endothelial Cells Correlates with Long-term Survival of Patients with Renal Cell Carcinoma

Authors' Affiliations: ¹ Tumor Immunology Laboratory, LIFE Center, Departments of ² Urology and ³ Surgery, University Clinic Grosshadern, ⁴ Institute of Pathology, Ludwig-Maximilians-University Munich, Munich, Germany; ⁵ Institute for Molecular Immunology, GSF National Research Center for the Environment and Health, Neuherberg, Germany; and ⁶ Laboratory of Radiation Safety, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Gengo, Morioka, Obu, Aichi, Japan

Requests for reprints: Wolfgang Zimmermann, Tumor Immunology Laboratory, LIFE Center, University Clinic Grosshadern, Ludwig-Maximilians-University München, Marchioninistrasse 23, D-81377 Munich, Germany. Phone: 49-89-7095-4895; Fax: 49-89-7095-4864; E-mail: wolfgang.zimmermann{at}med.uni-muenchen.de.

Purpose: The inflammatory enzyme indoleamine 2,3-dioxygenase (IDO) participates in immune tolerance and tumor immune escape processes by degradation of the essential amino acid tryptophan and formation of toxic catabolites. Here, we analyzed the role of IDO in tumor growth and disease progression in patients with clear cell renal cell carcinoma (RCC).

Experimental Design: Expression of IDO mRNA was analyzed by quantitative reverse transcription-PCR in 55 primary and 52 metastatic RCC, along with 32 normal kidneys. Western blot and immunohistochemistry analyses were used to semiquantitatively determine IDO proteins in a subset of tumor samples, in RCC cell lines, and microvessel endothelial cells. IDO expression was correlated with expression of the proliferation marker Ki67 in tumor cells and survival of patients with tumor.

Results: More than 75% of the clear cell RCC in comparison to normal kidney contained elevated levels of IDO mRNA, which correlated with their IDO protein content. Low IDO mRNA levels in primary tumors represented an unfavorable independent prognostic factor (hazard ratio, 3.8; P = 0.016). Unexpectedly, immunohistochemical analyses revealed that IDO is nearly exclusively expressed in endothelial cells of newly formed blood vessels and is virtually absent from tumor cells, although RCC cells could principally synthesize IDO as shown by in vitro stimulation with IFN-. A highly significant inverse correlation between the density of IDO-positive microvessels and the content of proliferating Ki67-positive tumor cells in primary and metastatic clear cell RCC was found (P = 0.004).

Conclusions: IDO in endothelial cells might limit the influx of tryptophan from the blood to the tumor or generate tumor-toxic metabolites, thus restricting tumor growth and contributing to survival.