Exhaustion of CD4+ T-cells mediated by the Kynurenine Pathway in Melanoma

Soudabeh Rad Pour*, Hiromasa Morikawa, Narsis A Kiani, Muyi Yang, Alireza Azimi, Gowhar Shafi, Mingmei Shang, Roland Baumgartner, Daniel F J Ketelhuth, Muhammad Anas Kamleh, Craig E Wheelock, Andreas Lundqvist, Johan Hansson, Jesper Tegnér

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

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 IFNγ, 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.

Original languageEnglish
Article number12150
JournalScientific Reports
Volume9
Issue number1
Number of pages11
ISSN2045-2322
DOIs
Publication statusPublished - 21. Aug 2019
Externally publishedYes

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    Rad Pour, S., Morikawa, H., Kiani, N. A., Yang, M., Azimi, A., Shafi, G., Shang, M., Baumgartner, R., Ketelhuth, D. F. J., Kamleh, M. A., Wheelock, C. E., Lundqvist, A., Hansson, J., & Tegnér, J. (2019). Exhaustion of CD4+ T-cells mediated by the Kynurenine Pathway in Melanoma. Scientific Reports, 9(1), [12150]. https://doi.org/10.1038/s41598-019-48635-x