Mitochondrial arginase-2 is a cell‑autonomous regulator of CD8+ T cell function and antitumor efficacy

Article Article scientifique Article Mitochondrial arginase-2 is a cell‑autonomous regulator of CD8+ T cell function and antitumor efficacy eng 2019 author Marti Lindez Adria-Arnau 826235 author Dunand-Sauthier Isabelle 134225 author Conti Mark 754695 author Gobet Florian 631681 author Núñez Nicolás author Hannich Joerg Thomas 693454 author Riezman Howard 134430 author Geiger Roger author Piersigilli Alessandra author Hahn Kerstin author Lemeille Sylvain 637517 author Becher Burkhard author De Smedt Thibaut 832144 author Hugues Stéphanie 663452 author Reith Walter 25482 10.1172/jci.insight.132975 31751318 2379-3708 As sufficient extracellular arginine is crucial for T cell function, depletion of extracellular arginine by elevated arginase 1 (Arg1) activity has emerged as a hallmark immunosuppressive mechanism. However, the potential cell-autonomous roles of arginases in T cells have remained unexplored. Here, we show that the arginase isoform expressed by T cells, the mitochondrial Arg2, is a cell-intrinsic regulator of CD8+ T cell activity. Both germline Arg2 deletion and adoptive transfer of Arg2-/- CD8+ T cells significantly reduced tumor growth in preclinical cancer models by enhancing CD8+ T cell activation, effector function, and persistence. Transcriptomic, proteomic, and high-dimensional flow cytometry characterization revealed a CD8+ T cell-intrinsic role of Arg2 in modulating T cell activation, antitumor cytoxicity, and memory formation, independently of extracellular arginine availability. Furthermore, specific deletion of Arg2 in CD8+ T cells strongly synergized with PD-1 blockade for the control of tumor growth and animal survival. These observations, coupled with the finding that pharmacologic arginase inhibition accelerates activation of ex vivo human T cells, unveil Arg2 as a potentially new therapeutic target for T cell-based cancer immunotherapies. Dewey 540 Dewey 616.07 Swiss National Science Foundation Expression, function and mechanism of action of BTN2A2, a new costimulatory molecule coregulated with MHC class II expression 166371 CH Project funding 39 Département de biochimie 144 137 Département de pathologie et immunologie 21F false 124 Groupe Pierre Burkhard (neurologie) 154 221 Groupe Reith Walter (pathologie et immunologie) 282 JCI Insight 4 24 9b035f95-4232-479e-bac2-a3c3bf0898fd Article (Published version) Public 132975.2-20191127153651-covered-253bed37ca4c1ab43d105aefdf7b5536.pdf 7433558 application/pdf OA OTHER openAccess Faculté des sciences / Section de chimie et biochimie / Département de biochimie Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie

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Mitochondrial arginase-2 is a cell‑autonomous regulator of CD8+ T cell function and antitumor efficacy	JCI Insight			2019	394	291

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