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Mitochondrial Arginase-2 is a cell autonomous regulator of CD8+ T cell function and anti-tumor efficacy.

Authors
  • Martí I Líndez, Adrià-Arnau
  • Dunand-Sauthier, Isabelle
  • Conti, Mark
  • Gobet, Florian
  • Núñez, Nicolás
  • Hannich, J Thomas
  • Riezman, Howard
  • Geiger, Roger
  • Piersigilli, Alessandra
  • Hahn, Kerstin
  • Lemeille, Sylvain
  • Becher, Burkhard
  • De Smedt, Thibaut
  • Hugues, Stéphanie
  • Reith, Walter
Type
Published Article
Journal
JCI Insight
Publisher
American Society for Clinical Investigation
Publication Date
Nov 21, 2019
Identifiers
DOI: 10.1172/jci.insight.132975
PMID: 31751318
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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 Arginase 2 (Arg2), is a cell-intrinsic regulator of CD8+ T cell activity. Both germ-line 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, anti-tumor 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 new therapeutic target for T cell-based cancer therapies.

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