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Indoleamine 2,3-Dioxygenase Expression Pattern in the Tumor Microenvironment Predicts Clinical Outcome in Early Stage Cervical Cancer
The indoleamine 2,3-dioxygenase (IDO) enzyme can act as an immunoregulator by inhibiting T cell function via the degradation of the essential amino acid tryptophan (trp) into kynurenine (kyn) and its derivates. The kyn/trp ratio in serum is a prognostic factor for cervical cancer patients; however,...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050387/ https://www.ncbi.nlm.nih.gov/pubmed/30050535 http://dx.doi.org/10.3389/fimmu.2018.01598 |
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author | Heeren, A. Marijne van Dijk, Ilse Berry, Daniella R. A. I. Khelil, Maryam Ferns, Debbie Kole, Jeroen Musters, René J. P. Thijssen, Victor L. Mom, Constantijne H. Kenter, Gemma G. Bleeker, Maaike C. G. de Gruijl, Tanja D. Jordanova, Ekaterina S. |
author_facet | Heeren, A. Marijne van Dijk, Ilse Berry, Daniella R. A. I. Khelil, Maryam Ferns, Debbie Kole, Jeroen Musters, René J. P. Thijssen, Victor L. Mom, Constantijne H. Kenter, Gemma G. Bleeker, Maaike C. G. de Gruijl, Tanja D. Jordanova, Ekaterina S. |
author_sort | Heeren, A. Marijne |
collection | PubMed |
description | The indoleamine 2,3-dioxygenase (IDO) enzyme can act as an immunoregulator by inhibiting T cell function via the degradation of the essential amino acid tryptophan (trp) into kynurenine (kyn) and its derivates. The kyn/trp ratio in serum is a prognostic factor for cervical cancer patients; however, information about the relationship between serum levels and IDO expression in the tumor is lacking. IDO expression was studied in 71 primary and 14 paired metastatic cervical cancer samples by various immunohistochemical (IHC) techniques, including 7-color fluorescent multiparameter IHC, and the link between the concentration of IDO metabolites in serum, clinicopathological characteristics, and the presence of (proliferating) T cells (CD8, Ki67, and FoxP3) was examined. In addition, we compared the relationships between IDO1 and IFNG gene expression and clinical parameters using RNAseq data from 144 cervical tumor samples published by The Cancer Genome Atlas (TCGA). Here, we demonstrate that patchy tumor IDO expression is associated with an increased systemic kyn/trp ratio in cervical cancer (P = 0.009), whereas marginal tumor expression at the interface with the stroma is linked to improved disease-free (DFS) (P = 0.017) and disease-specific survival (P = 0.043). The latter may be related to T cell infiltration and localized IFNγ release inducing IDO expression. Indeed, TCGA analysis of 144 cervical tumor samples revealed a strong and positive correlation between IDO1 and IFNG mRNA expression levels (P < 0.001) and a significant association with improved DFS for high IDO1 and IFNG transcript levels (P = 0.031). Unexpectedly, IDO+ tumors had higher CD8(+)Ki67(+) T cell rates (P = 0.004). Our data thus indicate that the serum kyn/trp ratio and IDO expression in primary tumor samples are not clear-cut biomarkers for prognosis and stratification of patients with early stage cervical cancer for clinical trials implementing IDO inhibitors. Rather, a marginal IDO expression pattern in the tumor dominantly predicts favorable outcome, which might be related to IFNγ release in the cervical tumor microenvironment. |
format | Online Article Text |
id | pubmed-6050387 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-60503872018-07-26 Indoleamine 2,3-Dioxygenase Expression Pattern in the Tumor Microenvironment Predicts Clinical Outcome in Early Stage Cervical Cancer Heeren, A. Marijne van Dijk, Ilse Berry, Daniella R. A. I. Khelil, Maryam Ferns, Debbie Kole, Jeroen Musters, René J. P. Thijssen, Victor L. Mom, Constantijne H. Kenter, Gemma G. Bleeker, Maaike C. G. de Gruijl, Tanja D. Jordanova, Ekaterina S. Front Immunol Immunology The indoleamine 2,3-dioxygenase (IDO) enzyme can act as an immunoregulator by inhibiting T cell function via the degradation of the essential amino acid tryptophan (trp) into kynurenine (kyn) and its derivates. The kyn/trp ratio in serum is a prognostic factor for cervical cancer patients; however, information about the relationship between serum levels and IDO expression in the tumor is lacking. IDO expression was studied in 71 primary and 14 paired metastatic cervical cancer samples by various immunohistochemical (IHC) techniques, including 7-color fluorescent multiparameter IHC, and the link between the concentration of IDO metabolites in serum, clinicopathological characteristics, and the presence of (proliferating) T cells (CD8, Ki67, and FoxP3) was examined. In addition, we compared the relationships between IDO1 and IFNG gene expression and clinical parameters using RNAseq data from 144 cervical tumor samples published by The Cancer Genome Atlas (TCGA). Here, we demonstrate that patchy tumor IDO expression is associated with an increased systemic kyn/trp ratio in cervical cancer (P = 0.009), whereas marginal tumor expression at the interface with the stroma is linked to improved disease-free (DFS) (P = 0.017) and disease-specific survival (P = 0.043). The latter may be related to T cell infiltration and localized IFNγ release inducing IDO expression. Indeed, TCGA analysis of 144 cervical tumor samples revealed a strong and positive correlation between IDO1 and IFNG mRNA expression levels (P < 0.001) and a significant association with improved DFS for high IDO1 and IFNG transcript levels (P = 0.031). Unexpectedly, IDO+ tumors had higher CD8(+)Ki67(+) T cell rates (P = 0.004). Our data thus indicate that the serum kyn/trp ratio and IDO expression in primary tumor samples are not clear-cut biomarkers for prognosis and stratification of patients with early stage cervical cancer for clinical trials implementing IDO inhibitors. Rather, a marginal IDO expression pattern in the tumor dominantly predicts favorable outcome, which might be related to IFNγ release in the cervical tumor microenvironment. Frontiers Media S.A. 2018-07-11 /pmc/articles/PMC6050387/ /pubmed/30050535 http://dx.doi.org/10.3389/fimmu.2018.01598 Text en Copyright © 2018 Heeren, van Dijk, Berry, Khelil, Ferns, Kole, Musters, Thijssen, Mom, Kenter, Bleeker, de Gruijl and Jordanova. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Heeren, A. Marijne van Dijk, Ilse Berry, Daniella R. A. I. Khelil, Maryam Ferns, Debbie Kole, Jeroen Musters, René J. P. Thijssen, Victor L. Mom, Constantijne H. Kenter, Gemma G. Bleeker, Maaike C. G. de Gruijl, Tanja D. Jordanova, Ekaterina S. Indoleamine 2,3-Dioxygenase Expression Pattern in the Tumor Microenvironment Predicts Clinical Outcome in Early Stage Cervical Cancer |
title | Indoleamine 2,3-Dioxygenase Expression Pattern in the Tumor Microenvironment Predicts Clinical Outcome in Early Stage Cervical Cancer |
title_full | Indoleamine 2,3-Dioxygenase Expression Pattern in the Tumor Microenvironment Predicts Clinical Outcome in Early Stage Cervical Cancer |
title_fullStr | Indoleamine 2,3-Dioxygenase Expression Pattern in the Tumor Microenvironment Predicts Clinical Outcome in Early Stage Cervical Cancer |
title_full_unstemmed | Indoleamine 2,3-Dioxygenase Expression Pattern in the Tumor Microenvironment Predicts Clinical Outcome in Early Stage Cervical Cancer |
title_short | Indoleamine 2,3-Dioxygenase Expression Pattern in the Tumor Microenvironment Predicts Clinical Outcome in Early Stage Cervical Cancer |
title_sort | indoleamine 2,3-dioxygenase expression pattern in the tumor microenvironment predicts clinical outcome in early stage cervical cancer |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050387/ https://www.ncbi.nlm.nih.gov/pubmed/30050535 http://dx.doi.org/10.3389/fimmu.2018.01598 |
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