IL4-induced gene 1 promotes tumor growth by shaping the immune microenvironment in melanoma

Bod, Lloyd; Lengagne, Renée; Wrobel, Ludovic J.; Ramspott, Jan Philipp; Kato, Masashi; Avril, Marie-Françoise; Castellano, Flavia; Molinier‐Frenkel, Valérie; Prévost-Blondel, Armelle

doi:10.1080/2162402x.2016.1278331

Cited by 27 publications

(38 citation statements)

References 30 publications

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“…Preclinical models indicate that IDO1 expression and IL4I1 can promote tumor escape from the immune system, as both enzymes decrease the antitumor cytotoxic T‐cell response and favor tumor growth in mouse models. Consistent with these results, we recently observed that tumor growth was more easily controlled in the absence of the enzyme in IL4I1 KO mice ( and unpublished data). Moreover, the absence of IL4I1 delayed primary tumor growth and metastases in a mouse model of spontaneous melanoma dependent on the Ret oncogene.…”

Section: Role Of Amino Acid‐catabolizing Enzymes In Cancersupporting

confidence: 85%

“…Moreover, the absence of IL4I1 delayed primary tumor growth and metastases in a mouse model of spontaneous melanoma dependent on the Ret oncogene. Modifications of the primary tumor infiltrate, characterized by increased Th1 and cytotoxic T lymphocytes and decreased polymorphonuclear MDSCs, accompanied this delay [81]. Many studies have sought a clinical correlation between the expression of these enzymes and the prognosis of cancer patients.…”

Section: Role Of Amino Acid-catabolizing Enzymes In Cancermentioning

confidence: 99%

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Immunosuppressive enzymes in the tumor microenvironment

Molinier‐Frenkel

Castellano

2017

FEBS Letters

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Antigen encounter by T lymphocytes induces important metabolic changes. Antitumor T lymphocytes enter in a metabolic competition with tumors, which divert feedback mechanisms of the immune response. Immunosuppressive enzymes, modifying the nutrient availability and leading to the production of toxic catabolites, represent one of these mechanisms, contributing to the metabolic halo in which T lymphocytes evolve during immune responses. Two classes of immunosuppressive enzymes, expressed by the tumor cells or by cells of the microenvironment, have been described: those catabolizing essential or semiessential amino acids, tryptophan, arginine, and phenylalanine and the ectoenzymes, which degrade the ATP to produce adenosine. These enzymes are described, as well as some of the ongoing clinical trials aiming to block them in cancer treatment.

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Section: Role Of Amino Acid‐catabolizing Enzymes In Cancersupporting

confidence: 85%

Section: Role Of Amino Acid-catabolizing Enzymes In Cancermentioning

confidence: 99%

Immunosuppressive enzymes in the tumor microenvironment

Molinier‐Frenkel

Castellano

2017

FEBS Letters

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“…This pattern of expression suggests a role in the negative control of the T‐cell response, as IL4I1 inhibits T lymphocyte proliferation and biases naive T‐cell differentiation towards that of FoxP3 + regulatory T cells in vitro . IL4I1 is also expressed by human tumor‐associated macrophages and may participate in immune escape, as it facilitates tumor growth by dampening the anti‐tumor T‐cell response . Finally, the IL4I1 enzyme (or the IL4I1 mRNA) has been observed in several B‐ and T‐cell subpopulations, in particular T helper type 17 T cells (Th17) , where its production may be induced in an autocrine manner .…”

Section: Introductionmentioning

confidence: 99%

IL4‐induced gene 1 is secreted at the immune synapse and modulates TCR activation independently of its enzymatic activity

et al. 2017

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Amino-acid catabolizing enzymes produced by mononuclear phagocytes play a central role in regulating the immune response. The mammalian phenylalanine-catabolizing enzyme IL4-induced gene 1 (IL4I1) inhibits effector T lymphocyte proliferation and facilitates regulatory T-cell development. IL4I1 expression by macrophages of various human tumors may affect patient prognosis as it facilitates tumor escape from the T-cell response in murine models. Its enzymatic activity appears to participate in its effects, but some actions of IL4I1 remain unclear. Here, we show that the presence of IL4I1 during T-cell activation decreases early signaling events downstream of TCR stimulation, resulting in global T-cell inhibition which is more pronounced when there is CD28 costimulation. Surprisingly, the enzymatic activity of IL4I1 is not involved. Focal secretion of IL4I1 into the immune synaptic cleft and its binding to CD3 + lymphocytes could be important in IL4I1 immunosuppressive mechanism of action. Keywords: CD28 stimulation r Immunosuppressive enzymes r T cells r TCR signalingAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionClonotypic TCR engagement by antigen presenting cells via the MHC/peptide complex is the central event of T-cell activation.Correspondence: Dr. Flavia Castellano and Dr. Valérie Molinier-Frenkel e-mail: flavia.castellano@inserm.fr; valerie.frenkel@inserm.fr TCR signaling consists of a molecular cascade propagated from the cytosol to the nucleus via a multilayered signal-transduction network. This network involves proximal kinases, such as Lck and ZAP70, and a molecular platform of adaptor proteins, such as LAT * These authors contributed equally to this work.C 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2018. 48: 106-119 Molecular immunology and signaling 107 Figure 1. IL4I1 decreases early TCR signaling. (A & B) CD3+ T lymphocytes obtained by negative sorting were stimulated with an anti-CD3 mAb alone (A) or together with an anti-CD28 mAb (B) in conditioned media from HEK cells that produce IL4I1 (IL4I1) or those that do not (Ctrl) for 0 (unstimulated), 1, or 2 min. Cell lysates were analyzed by western blotting with an anti-phospho-ZAP70 mAb (Y319). One representative experiment is shown in the upper panels. Relative quantification of the bands (ratio phospho-ZAP70 to total ZAP70) is shown in the lower panels (A and B: average of 3 and 5 independent experiments, respectively). (C) Western blot analysis of phosphorylated ZAP70 (Y319), ERK p42 (T202/Y204), and p44 (T185/Y187) after activation of T cells as in B, with 100 ng purified recombinant IL4I1 (rIL4I1) or without (Ctrl) for 0 (unstimulated), 2, or 5 min. One representative experiment of 3 independent experiments is shown. Numbers under each blot represent the OD ratios of the respective phosphorylated protein over total Western blot analysis of phosphorylated PLC-γ (Y783) after T-cell activation as in A and B, respectively, in c...

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“…IL4I1 has been detected in murine FO B cells (23), and interestingly its overexpression seems to be associated with a better outcome in human FO lymphoma (24). More recently we have shown that IL4I1 reduces the tumor infiltration by B cells in a mouse model of spontaneous melanoma (25). Nevertheless, the role of IL4I1 in B cell physiology remains to be established.…”

mentioning

confidence: 97%

IL-4–Induced Gene 1: A Negative Immune Checkpoint Controlling B Cell Differentiation and Activation

Bod¹,

Douguet²,

Auffray³

et al. 2018

The Journal of Immunology

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Emerging data highlight the crucial role of enzymes involved in amino acid metabolism in immune cell biology. IL-4-induced gene-1 (IL4I1), a secreted l-phenylalanine oxidase expressed by APCs, has been detected in B cells, yet its immunoregulatory role has only been explored on T cells. In this study, we show that IL4I1 regulates multiple steps in B cell physiology. Indeed, IL4I1 knockout mice exhibit an accelerated B cell egress from the bone marrow, resulting in the accumulation of peripheral follicular B cells. They also present a higher serum level of natural Igs and self-reactive Abs. We also demonstrate that IL4I1 produced by B cells themselves controls the germinal center reaction, plasma cell differentiation, and specific Ab production in response to T dependent Ags, SRBC, and NP-KLH. In vitro, IL4I1-deficient B cells proliferate more efficiently than their wild-type counterparts in response to BCR cross-linking. Moreover, the absence of IL4I1 increases activation of the Syk-Akt-S6kinase signaling pathway and calcium mobilization, and inhibits SHP-1 activity upon BCR engagement, thus supporting that IL4I1 negatively controls BCR-dependent activation. Overall, our study reveals a new perspective on IL4I1 as a key regulator of B cell biology.

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IL4-induced gene 1 promotes tumor growth by shaping the immune microenvironment in melanoma

Cited by 27 publications

References 30 publications

Immunosuppressive enzymes in the tumor microenvironment

Immunosuppressive enzymes in the tumor microenvironment

IL4‐induced gene 1 is secreted at the immune synapse and modulates TCR activation independently of its enzymatic activity

IL-4–Induced Gene 1: A Negative Immune Checkpoint Controlling B Cell Differentiation and Activation

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