Cancer Letters

Cancer Letters

Volume 223, Issue 2, 8 June 2005, Pages 323-329
Cancer Letters

Tryptophan degradation in patients with gynecological cancer correlates with immune activation

https://doi.org/10.1016/j.canlet.2004.10.033Get rights and content

Abstract

Tryptophan degradation by the enzyme indoleamine-(2,3)-dioxy genase (IDO) and neopterin production are induced within cellular immune activation by stimulation of monocyte-derived macrophages and dendritic cells with cytokine interferon-γ. Deprivation of tryptophan represents an important antimicrobial and antitumoral immune defence mechanism but it also suppresses T-cell proliferation. Recently tryptophan degradation by tumor cells was proposed as strategy to escape immune response.

In this study the relationship between tryptophan degradation and immune activation was examined in 20 patients with gynecological cancer. Concentrations of tryptophan and kynurenine were measured by HPLC in sera of patients, and to estimate IDO activity, the kynurenine to tryptophan ratio was calculated. In parallel, neopterin concentrations were measured by ELISA.

Tryptophan concentrations (median, interquartile range: 43.5, 31.2–56.3 μM) were lower in patients with gynecological cancer compared to healthy individuals of similar age (53.5, 47.0–64.2 μM; P<0.05). Kynurenine concentrations (median: 1.91 vs. 1.73 μM in controls) and kyn/trp (median: 41 vs. 35 μmol/mmol in controls) were slightly higher in patients, but not significantly different. Neopterin concentrations were significantly higher in patients (median: 10.8 vs. 7.0 nM in controls; P<0.05) and correlated with the kynurenine per tryptophan ratio (rs=0.555; P<0.02).

In conclusion, tryptophan degradation is detectable in patients with gynecological cancer. The relationship between kyn/trp and neopterin concentrations indicates that cellular immune activation rather than tumor-mediated IDO-activity is responsible (228 words).

Introduction

Enzyme indolamine-2,3-dioxygenase (IDO) is inducible by cytokine interferon-γ (IFN-γ) and converts tryptophan to kynurenine [1], [2]. Degradation of the essential amino acid tryptophan leads to reduced availability and is considered as an immune defence mechanism, which suppresses the growth of intracellular bacteria, viruses and parasites like toxoplasma [3], [4] and of malignant tumor cells [2]. But also T-cell proliferation can be inhibited by IDO activity [5], immune response may be suppressed when tryptophan is diminished due to activated IDO.

In human monocyte-derived macrophages and dendritic cells, IDO activity coincides with enhanced neopterin production, both pathways are induced in parallel by the pro-inflammatory cytokine interferon-γ [6], [7]. Likewise, in several groups of patients, e.g. suffering from virus infections, autoimmune syndromes and also coronary heart disease, enhanced tryptophan degradation in parallel with increased neopterin formation was demonstrated [8], [9], [10]. Also in patients suffering from malignant diseases, e.g. hematological neoplasias [11], adult T-cell leukemia [12], gastrointestinal cancer [13] and with colorectal cancer [14], an increased tryptophan degradation and elevated neopterin concentrations was observed. In patients with T-cell leukemia and with colorectal cancer, accelerated degradation of tryptophan predicted shortened survival [12], [14]. Enhanced degradation of tryptophan and increased formation of neopterin in cancer patients appear to indicate activation of the cellular immune system and endogenous formation of cytokine IFN-γ, most likely related to host immune response against the tumor. However, IFN-γ is also capable of inducing IDO in tumor cell lines [15], [16], [17]. Recently tryptophan degradation by IDO was suggested as intrinsic tumoral immune resistance mechanism [17], tumor cells spontaneously expressing IDO were proposed to suppress T-cell proliferation and immune response by tryptophan depletion. In this study, the relationship between tryptophan degradation and neopterin concentrations was examined in patients suffering from advanced gynecological cancer.

Section snippets

Patients

Twenty female patients (mean age: 70; SD: 12 years) with gynecological cancer were recruited from the district hospital of Eisenstadt, Austria. From 13 patients blood was taken before treatment against the tumor, the other seven samples were taken from patients who had relapsing disease. Seven patients died within the course of the study. Eleven patients had ovarian cancer, of these one patient was FIGO stage Ia, six patients were stage III and four patients were stage IV. Five patients

Results

Tryptophan concentrations in patients (median, interquartile range: 43.5, 31.2–56.3 μM]) were significantly lower than in controls (53.5, 46.9–64.2; P<0.05). Kynurenine concentrations (median: 1.91 vs. 1.73 μM in controls) and kyn/trp (median: 41.4 vs. 35.1 μmol/mmol in controls) were slightly higher in patients, but not significantly different. Neopterin concentrations were significantly higher in patients (median, interquartile range: 10.8, 7.4–22.5 nM) in comparison to controls (median,

Discussion

This study shows that tryptophan metabolism is altered in patients suffering from gynecological cancer compared to healthy controls. Tryptophan concentrations were lower, and there was a tendency to higher kynurenine concentrations and kyn/trp, and this was especially true for patients suffering from ovarian cancer. Parallel increase of neopterin formation was observed in patients with gynecological cancer, and the association found between kyn/trp and neopterin indicates that immune

Acknowledgements

We thank Miss Astrid Haara for excellent technical assistance. This work was supported by the Austrian Federal Ministry of Social Affairs and Generations.

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