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

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.

Exploring the Etiological Links behind Neurodegenerative Diseases: Inflammatory Cytokines and Bioactive Kynurenines

“…Activation of the KYN pathway suppresses effector T cells and induces Tregs, leading immune status to a tolerogenic state [118]. Increased KYN mediates inhibition of IL-2 signaling to reduce CD4 + T-cell survival [119]. IDO-expressing cells promote the differentiation of CD4 + T cells into Tregs expressing cytotoxic T-lymphocyte-associated protein 4, which downregulates immune responses [120].…”

“…IDO-expressing cells promote the differentiation of CD4 + T cells into Tregs expressing cytotoxic T-lymphocyte-associated protein 4, which downregulates immune responses [120]. Furthermore, higher KYNA production and lower KMO expression lead to dysfunctional effector CD4 + T-cell response [119]. NAD + protects differentiated Th1, Th2, and Th17 from CD4 + T-cells, induces apoptosis of naïve CD4 + T-cells, and reduces the number of Tregs, but protects induced Tregs against apoptosis [121].…”

Are Kynurenines Accomplices or Principal Villains in Dementia? Maintenance of Kynurenine Metabolism

“…IDO-activated cells can transform the function of APCs producing pro-inflammatory cytokine, IL-12, into anti-inflammatory cytokines including TGF-β and IL−10 [86]. IDO increases the level of KYN, which mediates the inhibition of IL-2 signaling to reduce CD4 T-cell survival [87]. Binding to AhR, KYN induces the dendritic cell and macrophage differentiation, which initially induces a highly inflammatory CD4 + T-cell subset, Th17 cells, and then further differentiate into Tregs during the resolution of inflammation [88].…”

“…IDO-expressing cells promote the differentiation of CD4 + T cells into Treg cells expressing CTLA-4, which is a protein receptor that functions as an immune checkpoint and downregulates immune responses [90]. In addition, higher KYNA production and lower KMO expression are associated with another regulatory immune mechanism, contributing to dysfunctional effector CD4 + T-cell response [87]. NAD + induces the apoptosis of naïve CD4 + T-cells and reduces the number of Tregs, but it protects differentiated Th1, Th2, Th17, from CD4 + T-cells and induced Treg against apoptosis [91].…”

Kynurenine‐3‐monooxygenase: A new direction for the treatment in different diseases

“…It was revealed that AA was much more readily converted into 3-HANA in the brain (Maddison & Giorgini, 2015). When the immune system is activated, KMO is stimulated by cytokines in the periphery and brain, which activates inflammation-mediated dysregulation of the KP, producing neurogenic excitatory damage, which is responsible for many major brain diseases (Garrison et al, 2018), and the lower KMO expression and the higher KYNA production may contribute to dysfunctional effector CD4+ T-cell response (Rad Pour et al, 2019). In addition, KMO gets immune in neurons and astrocytes of most of the forebrain and spinal cord regions (Chiarugi, Cozzi, Ballerini, Massacesi, & Moroni, 2001).…”