Myeloid-derived Suppressor Cells Inhibit T-cell Activation by Depleting Cystine and Cysteine

Myeloid-derived suppressor cells (MDSC) are present in most cancer patients and are potent inhibitors of T-cell-mediated antitumor immunity. Their inhibitory activity is attributed to production of arginase, reactive oxygen species, inducible nitric oxide synthase, and interleukin-10. Here we show that MDSCs also block T-cell activation by sequestering cystine and limiting the availability of cysteine. Cysteine is an essential amino acid for T-cell activation because T cells lack cystathionase, which converts methionine to cysteine, and because they do not have an intact xc- transporter and therefore cannot import cystine and reduce it intracellularly to cysteine. T cells depend on antigen-presenting cells (APC), such as macrophages and dendritic cells, to export cysteine, which is imported by T cells via their ASC neutral amino acid transporter. MDSCs express the xc- transporter and import cystine; however, they do not express the ASC transporter and do not export cysteine. MDSCs compete with APC for extracellular cystine, and in the presence of MDSCs, APC release of cysteine is reduced, thereby limiting the extracellular pool of cysteine. In summary, MDSCs consume cystine and do not return cysteine to their microenvironment, thereby depriving T cells of the cysteine they require for activation and function.