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Immunosuppression associée à l’enzyme interleukine-4 induced gene 1 (IL4I1) : régulation de l’expression dans les cellules humaines et rôle dans l’échappement tumoral à la réponse immune dans un modèle murin

Abstract : The IL4I1 protein is a secreted L-amino acid oxidase, which inhibits T cell proliferationthrough phenylalanine degradation in vitro (Boulland et al, Blood 2007). Similar to previously describedimmunosuppressive enzymes, IL4I1 is expressed in cancer by myeloid cells and/or tumor cells(Carbonnelle-Puscian et al, Leukemia 2009). The aim of this work was to characterize the cells andstimuli associated with IL4I1 expression and to decipher its role in cancer.We showed that macrophages and dendritic cells are the main source of IL4I1 in vitro and inchronic inflammatory lesions. IL4I1 expression in mononuclear phagocytes is induced by interferons orTLR ligands, which act through STAT1 and NFkB respectively. Conversely, B cells express dramaticallylower levels of IL4I1 under the control of IL-4/STAT6 and CD40/NFkB. IL4I1 expression by monocyticcells inhibits the production of Th1 cytokines and may thus contribute to Th1 inflammation control invivo.In a murine model of cancer, IL4I1 expression facilitates tumor development by depressing thetumor specific cytotoxic T cell response. This is observed for IL4I1 activity levels in the range of thosemeasured in human tumors, suggesting that IL4I1 may contribute to tumor immune escape in humans.We developed several IL4I1 mutants to discriminate the role of the enzymatic activity versus the bindingto a putative cell surface receptor in the protumor effect observed. One of these mutants is currentlyavailable for in vivo testing.Our results definitively establish IL4I1 in the family of immunosuppressive enzymes associatedwith cancer and pave the way for the development of specific inhibitors as therapeutic tools
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Submitted on : Thursday, September 20, 2012 - 4:22:12 PM
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Fanette Lasoudris. Immunosuppression associée à l’enzyme interleukine-4 induced gene 1 (IL4I1) : régulation de l’expression dans les cellules humaines et rôle dans l’échappement tumoral à la réponse immune dans un modèle murin. Sciences agricoles. Université Paris-Est, 2011. Français. ⟨NNT : 2011PEST0089⟩. ⟨tel-00734087⟩

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