Regulatory myeloid cells paralyze T cells through cell–cell transfer of the metabolite methylglyoxal
- 23 April 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Immunology
- Vol. 21 (5), 555-566
- https://doi.org/10.1038/s41590-020-0666-9
Abstract
Regulatory myeloid immune cells, such as myeloid-derived suppressor cells (MDSCs), populate inflamed or cancerous tissue and block immune cell effector functions. The lack of mechanistic insight into MDSC suppressive activity and a marker for their identification has hampered attempts to overcome T cell inhibition and unleash anti-cancer immunity. Here, we report that human MDSCs were characterized by strongly reduced metabolism and conferred this compromised metabolic state to CD8+ T cells, thereby paralyzing their effector functions. We identified accumulation of the dicarbonyl radical methylglyoxal, generated by semicarbazide-sensitive amine oxidase, to cause the metabolic phenotype of MDSCs and MDSC-mediated paralysis of CD8+ T cells. In a murine cancer model, neutralization of dicarbonyl activity overcame MDSC-mediated T cell suppression and, together with checkpoint inhibition, improved the efficacy of cancer immune therapy. Our results identify the dicarbonyl methylglyoxal as a marker metabolite for MDSCs that mediates T cell paralysis and can serve as a target to improve cancer immune therapy.Keywords
Funding Information
- Deutsche Krebshilfe
- Australian Society for Fish Biology
- Ústav pro Nanomateriály, Pokrocilé Technologie a Inovace, Technické Univerzity v Liberci
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