title: L-glutamine is a key parameter in the immunosuppression phenomenon.
abstract: Suppression of tumour-specific T-cell functions by myeloid-derived suppressor cells (MDSCs) is a dominant mechanism of tumour escape. MDSCs express two enzymes, i.e. inducible nitric oxide synthase (iNOS) and arginase (ARG1), which metabolize the semi-essential amino acid L-arginine (L-Arg) whose bioavailability is crucial for T-cell proliferation and functions. Recently, we showed that glutaminolysis supports MDSC maturation process by ensuring the supply of intermediates and energy. In this work, we used an immortalized cell line derived from mouse MDSCs (MSC-1 cell line) to further investigate the role of L-glutamine (L-Gln) in the maintenance of MDSC immunosuppressive activity. Culturing MSC-1 cells in L-Gln-limited medium inhibited iNOS activity, while ARG1 was not affected. MSC-1 cells inhibited Jukat cell growth without any noticeable effect on their viability. The characterization of MSC-1 cell metabolic profile revealed that L-Gln is an important precursor of lactate production via the NADP(+)-dependent malic enzyme, which co-produces NADPH. Moreover, the TCA cycle activity was down-regulated in the absence of L-Gln and the cell bioenergetic status was deteriorated accordingly. This strongly suggests that iNOS activity, but not that of ARG1, is related to an enhanced central carbon metabolism and a high bioenergetic status. Taken altogether, our results suggest that the control of glutaminolysis fluxes may represent a valuable target for immunotherapy.
authors.affiliation: Department of Chemical Engineering, Ecole Polytechnique de Montréal, 2500 Chemin de Polytechnique, Montreal, Quebec, Canada H3T 1J4.
authors.forename: Ines
authors.initials: I
authors.lastname: Hammami
authors.forename: Jingkui
authors.initials: J
authors.lastname: Chen
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bronte
authors.forename: Gregory
authors.initials: G
authors.lastname: DeCrescenzo
authors.forename: Mario
authors.initials: M
authors.lastname: Jolicoeur
mesh_terms: D000818:Animals; D001119:Arginase / Q000378:metabolism; D002460:Cell Line; D002952:Citric Acid Cycle; D004734:Energy Metabolism; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance; D007165:Immunosuppression Therapy; D019169:Jurkat Cells; D051379:Mice; D022423:Myeloid Cells / Q000276:immunology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D019139:Tumor Escape
chemical_list: D005973:Glutamine; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D001119:Arginase