Control of T-Cell Activation and Signaling by Amino-Acid Catabolizing Enzymes

Castellano, Flavia; Molinier‐Frenkel, Valérie

doi:10.3389/fcell.2020.613416

Cited by 21 publications

(11 citation statements)

References 114 publications

(124 reference statements)

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“…4). 18 It was reported that HIV+ patients have a higher ratio of phenylalanine/tyrosine than healthy individuals, 19 and our results are in agreement which can be verified from the metabolite box plot in Fig. 2.…”

Section: Hiv Before Glutamine Administration (Bt) Versus the Same Pat...supporting

confidence: 90%

Metabolite variations in the sera of HIV+ patients after an oral administration of effervescent glutamine and in comparison to non-HIV individuals by NMR

et al. 2023

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Section: Hiv Before Glutamine Administration (Bt) Versus the Same Pat...supporting

confidence: 90%

Metabolite variations in the sera of HIV+ patients after an oral administration of effervescent glutamine and in comparison to non-HIV individuals by NMR

et al. 2023

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“…T cells are exquisitely sensitive to the deprivation of L-arginine, resulting in proliferative arrest (51) and, in the case of CD4 + cells, the promotion of Th2 and T reg phenotypes (52). Our scGEX data revealed that in our model of NB, Arg1 expression was restricted to monocytic cells, with minimal amounts detected within the tumor cells (Fig.…”

Section: Bone Marrow-derived Ccr2 + Myeloid Cells Drive Neuroblastomamentioning

confidence: 66%

Neuroblastoma Formation Requires Unconventional CD4 T Cells and Arginase-1–Dependent Myeloid Cells

et al. 2021

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Immune cells regulate tumor growth by mirroring their function as tissue repair organizers in normal tissues. To understand the different facets of immune-tumor collaboration through genetics, spatial transcriptomics, and immunological manipulation with non-invasive, longitudinal imaging, we generated a penetrant double oncogene-driven autochthonous model of neuroblastoma. Spatial transcriptomic analysis showed that CD4 + and myeloid populations colocalized within the tumor parenchyma, while CD8 + T cells and B cells were peripherally dispersed. Depletion of CD4 + T cells or CCR2 + macrophages, but not B cells, CD8 + , or NK cells, prevented tumor formation. Tumor CD4 + T cells displayed unconventional phenotypes and were clonotypically diverse and antigen-independent. Within the myeloid fraction, tumor growth required myeloid cells expressing arginase-1. Overall, these results demonstrate how argininemetabolizing myeloid cells conspire with pathogenic CD4 + T cells to create permissive conditions for tumor formation, suggesting that these pro-tumorigenic pathways could be disabled by targeting myeloid arginine metabolism. Statement of SignificanceA new model of human neuroblastoma provides ways to track tumor formation and expansion in living animals, allowing identification of CD4 + T cell and macrophage functions required for oncogenesis.

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“…11 Glioblastoma is particular in that it is suspected to be derived from neural stem cells 15 and isoform 2 of IL4I1 is expressed in several neural cell types, 16 with a still undefined function that may involve control of the level of neurotransmitter amines. 17,18 In the same work, they demonstrate for the first time that IL4I1 promotes glioblastoma motility in vitro, an effect that may be highly relevant for metastatic processes. Finally, their work brings new insights by proposing that the immunosuppressive effect of IL4I1 in tumors is mediated by activation of the ligand-activated transcription factor aryl hydrocarbon receptor (AHR).…”

Section: Introductionmentioning

confidence: 83%

What role for AHR activation in IL4I1-mediated immunosuppression ?

et al. 2021

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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.

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Control of T-Cell Activation and Signaling by Amino-Acid Catabolizing Enzymes

Cited by 21 publications

References 114 publications

Metabolite variations in the sera of HIV+ patients after an oral administration of effervescent glutamine and in comparison to non-HIV individuals by NMR

Metabolite variations in the sera of HIV+ patients after an oral administration of effervescent glutamine and in comparison to non-HIV individuals by NMR

Neuroblastoma Formation Requires Unconventional CD4 T Cells and Arginase-1–Dependent Myeloid Cells

What role for AHR activation in IL4I1-mediated immunosuppression ?

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