Abstract
► The absence of l-Gln inhibited iNOS activity, but not ARG1 one. ► MSC-1 cells were able to inhibit Jurkat cell growth, but not their viability. ► Absence of l-Gln down-regulated central carbon metabolism and l-Arg recycling. ► Absence of l-Gln deteriorated cell bioenergetic status. ► l-Gln is crucial for iNOS-mediated immunosuppression activity.
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.