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Exhaustion of CD4+T-cells mediated by the Kynurenine Pathway in Melanoma
Karolinska Inst, Ctr Mol Med, Dept Med, Unit Computat Med, SE-17176 Stockholm, Sweden.
King Abdullah Univ Sci & Technol, Biol & Environm Sci & Engn Div BESE, Comp Elect & Math Sci & Engn Div CEMSE, Thuwal 239556900, Saudi Arabia.ORCID iD: 0000-0002-6793-5885
Karolinska Inst, Ctr Mol Med, Dept Med, Unit Computat Med, SE-17176 Stockholm, Sweden;Karolinska Inst, Algorithm Dynam Lab, Unit Computat Med, Dept Med Solna,Ctr Mol Med, SE-17177 Stockholm, Sweden;SciLifeLab, SE-17177 Stockholm, Sweden.
Karolinska Univ Hosp, Dept Oncol Pathol, Stockholm, Sweden.
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 12150Article in journal (Refereed) Published
Abstract [en]

Kynurenine pathway (KP) activation by the enzymatic activity of indoleamine 2,3-dioxygenase1 (IDO1) and kynurenine (KYN) production represents an attractive target for reducing tumour progression and improving anti-tumour immunity in multiple cancers. However, immunomodulatory properties of other KP metabolites such as 3-hydroxy kynurenine (3-HK) and kynurenic acid (KYNA) are poorly understood. The association of the kynurenine metabolic pathway with T-cell status in the tumour microenvironment were characterized, using gene expression data of 368 cutaneous skin melanoma (SKCM) patients from the TCGA cohort. Based on the identified correlations, we characterized the production of KYN, 3-HK, and KYNA in vitro using melanoma-derived cell lines and primary CD4+ CD25- T-cells. Activation of the CD4+ T-cells produced IFN gamma, which yielded increased levels of KYN and KYNA. Concurrently, kynurenine 3-monooxygenase (KMO) expression and proliferation of CD4+ T-cells were reduced, whereas exhaustion markers such as PD-L1, AHR, FOXP3, and CTLA4 were increased. Additionally, an analysis of the correlation network reconstructed using TCGA-SKCM emphasized KMO and KYNU with high variability among BRAF wild-type compared with V600E, which underscored their role in distinct CD4+ T-cell behavior in tumour immunity. Our results suggest that, in addition to IDO1, there is an alternative immune regulatory mechanism associated with the lower KMO expression and the higher KYNA production, which contributes to dysfunctional effector CD4+ T-cell response.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2019. Vol. 9, article id 12150
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Immunology in the medical area
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URN: urn:nbn:se:uu:diva-393726DOI: 10.1038/s41598-019-48635-xISI: 000481999500004PubMedID: 31434983OAI: oai:DiVA.org:uu-393726DiVA, id: diva2:1355555
Available from: 2019-09-30 Created: 2019-09-30 Last updated: 2019-09-30Bibliographically approved

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