What role for AHR activation in IL4I1-mediated immunosuppression ?

Abstract

The amino-acid catabolizing enzyme Interleukin-4 induced gene 1 (IL4I1) remains poorly characterized despite it is emerging as a pertinent therapeutic target for cancer. IL4I1 is secreted in the synaptic cleft by antigen-presenting cells. It inhibits TCR signaling, modulates naïve T cell differentiation and limits effector T cell proliferation. IL4I1 expression in tumors shapes the tumor microenvironment and impairs the antitumor cytotoxic T cell response, thereby facilitating cancer immune escape. Several mechanisms participate in these effects. Recent data suggest a role of new IL4I1 metabolites in activation of the arylhydrocarbon receptor (AHR). Here, we observe that expression of IL4I1 is poorly correlated with that of validated targets of AHR in human cancers. Moreover, dendritic cells do not upregulate AHR target genes in relation with IL4I1 expression in vivo. Finally, IL4I1 activity toward tryptophan leading to production of AHR-activating products is very low, and should be negligible when tryptophan-degrading enzymes of higher affinity compete for the substrate. We recently showed that IL4I1 expression by dendritic cells directly regulates immune synapse formation and modulates the repertoire and memory differentiation of responding CD8 T cells after viral infection. Thus, IL4I1 may restrain tumor control through regulating the priming of tumor-specific CD8 T cells, independently of AHR activation.

Involvement of Kynurenine Pathway in Hepatocellular Carcinoma

“…An IL4I1-driven AhR activity though KYNA increases tumour cell motility and T-cell proliferation [112]. Given that the activity of IL4I1 is independent of the KP and can limit antitumor immune cell response [113], inhibiting the formation of KYNA metabolite either via the KP or through IL4I1 gene reaction may be necessary to block the activation of AhR in cancer.…”

Amino Acid-Metabolizing Enzymes in Advanced High-Grade Serous Ovarian Cancer Patients: Value of Ascites as Biomarker Source and Role for IL4I1 and IDO1

“…However, only IDO1 appeared to metabolize their common substrate, since levels of Trp downstream metabolites attributable to IL4I1 activity were not increased. Although it cannot be excluded that this observation may be related to the further metabolism of the Trp downstream metabolites, it also may reasonably be explained by an inability of IL4I1 to compete with IDO1 for their common substrate, as IL4I1 has a considerably lower affinity for Trp [40,47]. In contrast, IL4I1 may not experience significant competition from Phe-and Tyr-metabolizing enzymes, allowing efficient IL4I1-mediated conversion of these substrates.…”

IL4I1: a novel molecular biomarker represents an inflamed tumor microenvironment and precisely predicts the molecular subtype and immunotherapy response of bladder cancer

“…Moreover, IL4I1 is closely linked to tumor progression. It is considered a metabolic immune checkpoint, and IL4I1-mediated catabolism of tryptophan (Trp) produces indoles and kynurenic acid, which activate aromatic receptors (AHR), thereby promoting cancer cell movement and inhibiting adaptive immunity ( Sadik et al, 2020 ; Castellano et al, 2021 ). Excessive expression of IL4I1 has been detected in primary mediastinal B cell lymphoma, where it functions as a regulator of immune response by suppressing the proliferation of T lymphocytes ( Boulland et al, 2007 ).…”