High Indoleamine 2,3-Dioxygenase Is Correlated With Microvessel Density and Worse Prognosis in Breast Cancer.

Lijuan Wei,Menghui Li,Fangxuan Li,Shanshan Zhu,Xiubao Ren,Juntian Liu,Feng Wei

doi:10.3389/fimmu.2018.00724

Abstract

Indoleamine 2,3-dioxygenase (IDO), which catalyzes the breakdown of the essential amino acid tryptophan into kynurenine, is understood to have a key role in cancer immunotherapy. IDO has also received more attention because of its non-immune functions including regulating angiogenesis. The purpose of this study was to investigate the effects of IDO on microvessel density (MVD), and to explore its prognostic role in breast cancer. We showed IDO expression was positively correlated with MVD labeled by CD105 (MVD-CD105) rather than MVD labeled by CD31 (MVD-CD31) in breast cancer specimens. Both IDO expression and MVD-CD105 level were associated with initial TNM stage, histological grade, and tumor-draining lymph nodes (TDLNs) metastasis in breast cancer. In the prognostic analysis, TDLNs metastasis, an advanced TNM stage (III) and high histological grade (III) significantly predicted shorter survival in univariate analysis. Concentrating on IDO and MVD, the patients with IDO expression or high MVD level had poorer prognosis compared with no IDO expression [P = 0.047 for progress-free survival (PFS)] and low MVD level (P = 0.019 for OS); the patients with IDO expression and high MVD level had a tendency with shorter overall survival when compared with non IDO expression, low MVD level, or both (P = 0.062 for OS). In multivariate analysis, an advanced TNM stage (III) was significantly associated with shorter 5-year survival rate of PFS (HR: 0.126, 95% CI: 0.024–0.669, P = 0.015). In order to verify the phenomenon of IDO promoting angiogenesis, we contained the study in vitro. We detected the expression of IDO mRNA in breast cancer cell lines and measured the concentration of tryptophan and kynurenine in the supernatants of MCF-7 by high performance liquid chromatography. The ratio of Kyn and trp (kyn/trp) was calculated to estimate IDO-enzyme activity. MCF-7 cells, which produce high level of IDO and metabolize tryptophan, promoted human umbilical vein endothelial cells (HUVEC) proliferation significantly in co-culture system. Meanwhile IDO could upregulate the expression of CD105 in HUVEC, which was downregulated after adding IDO inhibitor, 1-methyl-d-trytophan. These results suggest that IDO could promote angiogenesis in breast cancer, providing a novel, potentially effective molecular or gene therapy target for angiogenesis inhibition in the future.

Highlights

Indoleamine 2,3-dioxygenase (IDO), which catalyzes the breakdown of the essential amino acid tryptophan into kynurenine, is understood to have a key role in cancer immunotherapy because of its role in enabling cancers to evade the immune system
Clusters of endothelial cells stained with CD105 or CD31 that were clearly separated from adjacent microvessel were considered microvessels
As one of several immune checkpoints involved in tumor immune escape, IDO has emerged as a key target in cancer therapy because of immunoregulatory roles associated with tryptophan metabolism

Summary

Introduction

Indoleamine 2,3-dioxygenase (IDO), which catalyzes the breakdown of the essential amino acid tryptophan into kynurenine, is understood to have a key role in cancer immunotherapy because of its role in enabling cancers to evade the immune system. Most studies have shown that high IDO expression in tumor tissues usually correlates with a significantly worse prognosis in patients [1, 2]. Microvessel density (MVD) has been associated with worse prognosis in different cancers, such as colorectal cancer [5], endometrial cancer [6], and esophageal carcinoma [7]. CD105 is a homodimeric transmembrane glycoprotein, which belongs to the zona pellucida family of extracellular proteins, is expressed in activated endothelial cells in culture and in tumor microvessels [9]. There was a statistically significant association between recurrence rates with CD105 but not with CD31 [11] It is still unclear which is a better marker for tumor progression and prognosis, CD31 or CD105

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