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Indoleamine-2,3 dioxygenase: a fate-changer of the tumor microenvironment.

ABSTRACT: Indoleamine-2,3 dioxygenase is a rate-limiting enzyme in the tryptophan catabolism in kynurenine pathways that has an immunosuppressive effect and supports cancer cells to evade the immune system in different cancer types. Diverse cytokines and pathways upregulate the production of indoleamine-2,3 dioxygenase enzymes in the tumor microenvironment and cause more production and activity of this enzyme. Ultimately, this situation results in anti-tumor immune suppression which is in favor of tumor growth. Several inhibitors such as 1-methyl-tryptophan have been introduced for indoleamine-2,3 dioxygenase enzyme and some of them are widely utilized in pre-clinical and clinical trials. Importantly at the molecular level, indoleamine-2,3 dioxygenase is positioned in a series of intricate signaling and molecular networks. Here, the main objective is to provide a focused view of indoleamine-2,3 dioxygenase enhancer pathways and propose further studies to cover the gap in available information on the function of indoleamine-2,3 dioxygenase enzyme in the tumor microenvironment.

SUBMITTER: Azimnasab-Sorkhabi P

PROVIDER: S-EPMC10202066 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Indoleamine-2,3 dioxygenase: a fate-changer of the tumor microenvironment.

Azimnasab-Sorkhabi Parviz P Soltani-Asl Maryam M Yoshinaga Túlio Teruo TT Zaidan Dagli Maria Lucia ML Massoco Cristina de Oliveira CO Kfoury Junior Jose Roberto JR

Molecular biology reports 20230522 7

Indoleamine-2,3 dioxygenase is a rate-limiting enzyme in the tryptophan catabolism in kynurenine pathways that has an immunosuppressive effect and supports cancer cells to evade the immune system in different cancer types. Diverse cytokines and pathways upregulate the production of indoleamine-2,3 dioxygenase enzymes in the tumor microenvironment and cause more production and activity of this enzyme. Ultimately, this situation results in anti-tumor immune suppression which is in favor of tumor g ...[more]

PMID: 37217614

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Project 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.

Dataset Information

Indoleamine-2,3 dioxygenase: a fate-changer of the tumor microenvironment.

Publications

Indoleamine-2,3 dioxygenase: a fate-changer of the tumor microenvironment.

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