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

Abstract

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-g. 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.

Extensive Profiling of the Expression of the Indoleamine 2,3-Dioxygenase 1 Protein in Normal and Tumoral Human Tissues

“…It is remarkable that normal kidneys do not host IDO1 þ blood vessels, as opposed to their malignant counterpart. IDO1 expression by endothelial cells was reported to be associated with a relatively more favorable prognosis in renal cell carcinomas, in contrast with other tumor types (43). Thus, treatment of kidney tumors with IDO1 inhibitors might result in paradoxical tumor-promoting effects.…”

Hydroxyamidine Inhibitors of Indoleamine-2,3-dioxygenase Potently Suppress Systemic Tryptophan Catabolism and the Growth of IDO-Expressing Tumors

“…Patient populations for these studies should be enriched for those where tumor cell expression of IDO has been seen and is correlated with poor prognosis, as anecdotal clinical evidence for prolonged survival in patients in whom IDO expression is restricted to the vasculature and immune cells has been reported (34,35). Designing a suitable trial for testing the utility of IDO1 inhibitors will be guided by the experience from the trials of other immunotherapeutic agents such as the CTLA4 blockers ipilimumab and tremelimumab.…”

High expression of indoleamine 2,3-dioxygenase gene in prostate cancer

“…Notably, IDO has been shown to be expressed at the protein level mainly by vascular endothelial cells in term placenta (Ligam et al, 2005) and in renal cell carcinoma (Riesenberg et al, 2007). Furthermore, inhibition of IDO activity is known to improve the ability of HUVEC cells to stimulate allogenic T cell responses, and HUVEC cells transfected with the IDO gene induce anergy in allospecific T cells (Beutelspacher et al, 2006).…”