TY - JOUR
T1 - Indoleamine 2,3-dioxygenase expression pattern in the tumor microenvironment predicts clinical outcome in early stage cervical cancer
AU - Heeren, A. Marijne
AU - van Dijk, Ilse
AU - Berry, Daniella R. A. I.
AU - Khelil, Maryam
AU - Ferns, Debbie
AU - Kole, Jeroen
AU - Musters, René J. P.
AU - Thijssen, Victor L.
AU - Mom, Constantijne H.
AU - Kenter, Gemma G.
AU - Bleeker, Maaike C. G.
AU - de Gruijl, Tanja D.
AU - Jordanova, Ekaterina S.
PY - 2018/7/11
Y1 - 2018/7/11
N2 - 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.
AB - 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.
KW - Cervical cancer
KW - Indoleamine 2,3-dioxygenase
KW - Kynurenine
KW - MRNA
KW - Serum
KW - T cells
KW - The Cancer Genome Atlas
KW - Tryptophan
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85049868866&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30050535
UR - http://www.scopus.com/inward/record.url?scp=85049868866&partnerID=8YFLogxK
U2 - https://doi.org/10.3389/fimmu.2018.01598
DO - https://doi.org/10.3389/fimmu.2018.01598
M3 - Article
C2 - 30050535
SN - 1664-3224
VL - 9
JO - Frontiers in immunology
JF - Frontiers in immunology
IS - JUL
M1 - 1598
ER -