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Baumann, T.* ; Dunkel, A.* ; Schmid, C.* ; Schmitt, S.* ; Hiltensperger, M.* ; Lohr, K.* ; Laketa, V.* ; Donakonda, S.* ; Ahting, U.* ; Lorenz-Depiereux, B. ; Heil, J.E.* ; Schredelseker, J.* ; Simeoni, L.* ; Fecher, C.* ; Körber, N. ; Bauer, T. ; Hüser, N.* ; Hartmann, D.* ; Laschinger, M.* ; Eyerich, K.* ; Eyerich, S. ; Anton, M.* ; Streeter, M.* ; Wang, T.* ; Schraven, B.* ; Spiegel, D.* ; Assaad, F.* ; Misgeld, T.* ; Zischka, H. ; Murray, P.J.* ; Heine, A.* ; Heikenwälder, M.* ; Korn, T.* ; Dawid, C.* ; Hofmann, T.* ; Knolle, P.A.* ; Höchst, B.*

Regulatory myeloid cells paralyze T cells through cell-cell transfer of the metabolite methylglyoxal.

Nat. Immunol. 21, 555-566 (2020)
Postprint DOI PMC
Open Access Green
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.Myeloid-derived suppressor cells (MDSCs) residing within tumors can impede immune responses. Knolle and colleagues show that MDSCs poison immune cells by producing methylglyoxal, which functionally alters their cellular metabolism and hence their effector responses.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Hepatocellular-carcinoma Patients; Suppressor-cells; Dicarbonyl Stress; Amine Oxidase; Effector; Immunotherapy; Aminoacetone; Inhibition; Glycation; Proteins
ISSN (print) / ISBN 1529-2908
e-ISSN 1529-2916
Zeitschrift Nature Immunology
Quellenangaben Band: 21, Heft: 5, Seiten: 555-566 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort 75 Varick St, 9th Flr, New York, Ny 10013-1917 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Human Genetics (IHG)
Institute of Virology (VIRO)
Institute for Allergy Research (IAF)
Institute of Molecular Toxicology and Pharmacology (TOXI)