Mitochondrial arginase-2 is a cell‑autonomous regulator of CD8+ T cell function and antitumor efficacy
Adrià-Arnau Martí i Líndez, Isabelle Dunand-Sauthier, Mark Conti, Florian Gobet, Nicolás Núñez, J. Thomas Hannich, Howard Riezman, Roger Geiger, Alessandra Piersigilli, Kerstin Hahn, Sylvain Lemeille, Burkhard Becher, Thibaut De Smedt, Stéphanie Hugues, Walter Reith
Adrià-Arnau Martí i Líndez, Isabelle Dunand-Sauthier, Mark Conti, Florian Gobet, Nicolás Núñez, J. Thomas Hannich, Howard Riezman, Roger Geiger, Alessandra Piersigilli, Kerstin Hahn, Sylvain Lemeille, Burkhard Becher, Thibaut De Smedt, Stéphanie Hugues, Walter Reith
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Research Article Immunology Oncology

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

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 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.

Authors

Adrià-Arnau Martí i Líndez, Isabelle Dunand-Sauthier, Mark Conti, Florian Gobet, Nicolás Núñez, J. Thomas Hannich, Howard Riezman, Roger Geiger, Alessandra Piersigilli, Kerstin Hahn, Sylvain Lemeille, Burkhard Becher, Thibaut De Smedt, Stéphanie Hugues, Walter Reith

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Figure 5

Endogenous Arg2 in CD8+ T cells is a cell-intrinsic regulator of their antitumor function.

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Endogenous Arg2 in CD8+ T cells is a cell-intrinsic regulator of their a...
(A) The scheme illustrates the experimental setting used in panels B–D, F, and G. Five days prior to adoptive T cell transfer, 0.5 × 106 MC38-OVA cells were implanted s.c. into WT host. At day 0, 1 × 106 to 1.5 × 106 CD8+ T cells isolated from naive WT or Arg2–/– mixed BM chimeric mice were adoptively transferred into the tumor-bearing mice. Control mice received no T cells. One day after T cell transfer, mice were immunized s.c. with OVA257–264 and CpG-B. (B) Tumor growth, (C) mouse survival, and (D) tumor clearance rates at day 40 were assessed (n = 12–15). (E) Tumor growth was assessed using a setting identical to that in A, except that tumor-bearing mice received naive or 6-day preactivated CD8+ T cells derived from WT or Arg2–/– OT-I mice (n = 11–12). Only mice transferred with naive cells were primed in vivo by s.c. immunization with CpG-B and OVA257–264. (F and G) t-SNE plots showing the FlowSOM-guided metaclustering gated on (F) TCRb+ T cells present in the TdLNs or gated on (G) CD45+ cells infiltrating the tumors of WT tumor-bearing mice having received WT (left) or Arg2–/– (right) OT-I cells. (B–E) Results were pooled from 2 or 3 independent experiments. Data is represented as mean ± SEM throughout. *P < 0.05, **P < 0.01, and ****P < 0.0001 (B and E: 2-way ANOVA) (C: log-rank Mantel-Cox test) (D: Fisher’s exact test).