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

Baumann, Tobias; Dunkel, Andreas; Schmid, Christian; Schmitt, Sabine; Hiltensperger, Michael; Lohr, Kerstin; Laketa, Vibor; Donakonda, Sainitin; Ahting, Uwe; Lorenz-Depiereux, Bettina; Heil, Jan E; Schredelseker, Johann; Simeoni, Luca; Fecher, Caroline; Körber, Nina; Bauer, Tanja; Hüser, Norbert; Hartmann, Daniel; Laschinger, Melanie; Eyerich, Kilian; Eyerich, Stefanie; Anton, Martina; Streeter, Matthew; Wang, Tina; Schraven, Burkhart; Spiegel, David; Assaad, Farhah; Misgeld, Thomas; Zischka, Hans; Murray, Peter J; Heine, Annkristin; Heikenwälder, Mathias; Korn, Thomas; Dawid, Corinna; Hofmann, Thomas; Knolle, Percy A; Höchst, Bastian     «

Baumann, Tobias; Dunkel, Andreas; Schmid, Christian; Schmitt, Sabine; Hiltensperger, Michael; Lohr, Kerstin; Laketa, Vibor; Donakonda, Sainitin; Ahting, Uwe; Lorenz-Depiereux, Bettina; Heil, Jan E; Schredelseker, Johann; Simeoni, Luca; Fecher, Caroline; Körber, Nina; Bauer, Tanja; Hüser, Norbert; Hartmann, Daniel; Laschinger, Melanie; Eyerich, Kilian; Eyerich, Stefanie; Anton, Martina; Streeter, Matthew; Wang, Tina; Schraven, Burkhart; Spiegel, David; Assaad, Farhah; Misgeld, Thomas; Zischka, Ha...     »

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.      «

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, the...     »