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

By M. Srivastava, P. Sinha, V. Clements, P. Rodriguez, S. Ostrand-Rosenberg. Cancer Research, 2009

921 citations recorded by the source corpus.

Myeloid-derived suppressor cells (MDSC) are present in most cancer patients and are potent inhibitors of T-cell-mediated anti-tumor immunity. Their inhibitory activity is attributed to production of arginase, reactive oxygen species, inducible nitric oxide synthase, and IL-10. We now report that MDSC 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. MDSC express the xc− transporter and import cystine; however, they do not express the ASC transporter and do not export cysteine. MDSC compete with APC for extracellular cystine, and in the presence of MDSC, APC release of cysteine is reduced, thereby limiting the extracellular pool of cysteine. Therefore, MDSC consume cystine and do not return cysteine to their microenvironment, thereby depriving T cells of the cysteine they require for activation and function.

Subfields: Immunology, Physiology

View Paper: https://www.semanticscholar.org/paper/2bd969aaeb50cd6c2be96694b696fbbcebd7b4f2

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In Immunology

1. Erika L. Pearce
2. Michael D. Buck
3. D. Gabrilovich
4. TA Wynn
5. D. Marvel
6. Edward J. Pearce
7. S. Galli
8. M. Gubin

In Physiology

1. Erika L. Pearce
2. S. Galli
3. TA Wynn
4. D. Gabrilovich
5. Edward J. Pearce
6. Michael D. Buck

Citations in the corpus

• Lung cancer: Biology and treatment options. (2015, background): “RTK ROS AdenoCA (1.5”
• Metabolic competition in the tumor microenvironment is a driver of cancer progression (2015, background): “, 2013), and others (Mellor and Munn, 2008; Mockler et al., 2014; Srivastava et al., 2010), have speculated that nutrient competition in the tumor microenvironment in vivo impacts T cell function.”
• The nature of myeloid-derived suppressor cells in the tumor microenvironment (2016, background): “These mechanisms include production of NO and ROS (including PNT) [12,44,81], and elimination of key nutrition factors needed for T cell proliferation by depleting L-arginine (via Arg1) [45], sequestering L-cysteine [46], or reducing local tryptophan levels due to the activity of indole amine 2,3 di”
• Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils (2011, background): “; depletion of cysteine and cystine by MDSCs also has been demonstrated to inhibit T cell functio”
• Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy (2022, background): “What’s more, MDSCs with high expression of the Xc- system consume extracellular cyst(e)ine, but do not transport cysteine to the microenvironment due to the lack of ASC transporter proteins, thereby depriving of the cyst(e)ine required for T cells activation.(249) Notably, the process of ferroptosis”
• Myeloid derived suppressor cells (2013, background): “Like l-arginine, MDSCs deplete the environment of cysteine, an amino acid essential for T-cell activation.(41) T cells depend upon extracellular sources because they lack both the enzyme to convert methionine to cysteine and the membrane transporter to import cystine for intracellular reduction to c”
• HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment (2010, background): “Extensive studies in recent years suggested several mechanisms of MDSC-mediated immune suppression that involve arginine (Bronte and Zanovello, 2005; Rodríguez and Ochoa, 2008) and cysteine (Srivastava et al., 2010) metabolism, expression of some surface molecules (Pan et al.”
• Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function (2010, background): “Several other suppressive mechanisms have recently been suggested: secretion of TGF β [18,19], induction of regulatory T cells [20–22], depletion of cysteine [23], upregulation of cyclooxygenase 2 (Cox2) and prostaglandin E2 (PGE2) [24].”
• Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. (2015, background): “Main factors implicated in MDSC-mediated immune suppression include expression of arginase (ARG1), inducible NOS (iNOS) (3–5), TGF-β (13–15), IL-10 (16), and COX2 (17–19), sequestration of cysteine (20), decreased expression of l-selectin by T cells (21), and induction of Tregs (22), among others.”