Indoleamine 2,3-Dioxygenase Expression Pattern in the Tumor Microenvironment Predicts Clinical Outcome in Early Stage Cervical Cancer
Autor: | A. Marijne Heeren, Ilse van Dijk, Daniella R. A. I. Berry, Maryam Khelil, Debbie Ferns, Jeroen Kole, René J. P. Musters, Victor L. Thijssen, Constantijne H. Mom, Gemma G. Kenter, Maaike C. G. Bleeker, Tanja D. de Gruijl, Ekaterina S. Jordanova |
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Přispěvatelé: | Medical oncology laboratory, CCA - Cancer biology and immunology, AII - Cancer immunology, Obstetrics and gynaecology, Physiology, Radiation Oncology, Amsterdam Reproduction & Development (AR&D), Pathology, ACS - Microcirculation, ACS - Atherosclerosis & ischemic syndromes, Graduate School, Obstetrics and Gynaecology |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
lcsh:Immunologic diseases. Allergy indoleamine 2 3-dioxygenase cervical cancer T cell mRNA Immunology T cells The Cancer Genome Atlas 03 medical and health sciences 0302 clinical medicine Immunology and Allergy Medicine tryptophan Indoleamine 2 3-dioxygenase Original Research Cervical cancer Tumor microenvironment business.industry FOXP3 medicine.disease Primary tumor kynurenine 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Cancer research Immunohistochemistry business lcsh:RC581-607 serum CD8 |
Zdroj: | Frontiers in Immunology, 9(JUL):1598. Frontiers Media S.A. Heeren, A M, van Dijk, I, Berry, D R A I, Khelil, M, Ferns, D, Kole, J, Musters, R J P, Thijssen, V L, Mom, C H, Kenter, G G, Bleeker, M C G, de Gruijl, T D & Jordanova, E S 2018, ' Indoleamine 2,3-dioxygenase expression pattern in the tumor microenvironment predicts clinical outcome in early stage cervical cancer ', Frontiers in Immunology, vol. 9, no. JUL, 1598 . https://doi.org/10.3389/fimmu.2018.01598 Frontiers in Immunology Frontiers in immunology, 9(JUL):1598. Frontiers Media S.A. Frontiers in Immunology, Vol 9 (2018) |
ISSN: | 1664-3224 |
Popis: | 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. |
Databáze: | OpenAIRE |
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