What role for AHR activation in IL4I1-mediated immunosuppression ? - Université Paris-Est-Créteil-Val-de-Marne Access content directly
Journal Articles OncoImmunology Year : 2021

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 aryl-hydrocarbon 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 towards 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.
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Dates and versions

hal-03244910 , version 1 (01-06-2021)

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Flavia Castellano, Armelle Prevost-Blondel, José L Cohen, Valérie Molinier-Frenkel. What role for AHR activation in IL4I1-mediated immunosuppression ?. OncoImmunology, 2021, 10 (1), pp.1924500. ⟨10.1080/2162402X.2021.1924500⟩. ⟨hal-03244910⟩
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