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 2

Arg2–/– mice control tumor growth more efficiently via enhanced cytotoxic CD8+ T cell function.

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Arg2–/– mice control tumor growth more efficiently via enhanced cytotox...
(A) Tumor growth and (B) mouse survival in MC38-OVA tumor-bearing WT or Arg2–/– mice treated with CD8+ T cell–depleting (αCD8α) or isotype control (IgG2a) antibodies (n = 18–21). (C) Tumor growth and (D) mouse survival were analyzed in MC38-OVA tumor-bearing WT or Arg2–/– mice treated with CD4+ T cell depleting (αCD4) or isotype control (IgG2b) antibodies (n = 11–12). (A–D) Mice received 4 mg/kg doses of depleting or control antibody at days –3, –1, 1, 4, 8, 11, 15, and 18 relative to tumor injection. (E) WT and Arg2–/– mice that had been immunized 6 days earlier with OVA257–264 and CpG-B were implanted with CTVlo control or CTVhi OVA257–264–loaded syngeneic splenocytes, and target cell clearance was evaluated in the spleens after 24 hours. (F and G) CTVlo control or CTVhi OVA257–264–loaded syngeneic splenocytes were transferred into 11-day (F) B16-OVA or (G) MC38-OVA tumor-bearing WT or Arg2–/– mice, and target cell clearance was evaluated after 24 hours in the tumor-draining lymph nodes (TdLNs) and contralateral nondraining lymph nodes (ndLNs). Target cell clearance in the TdLNs is expressed as killing ratio relative to the control cells and was normalized relative to the killing ratio in the ndLNs. (H) Naive WT or Arg2–/– mice received CTVlo control or CTVhi β2m–/– syngeneic splenocytes, and target cell clearance was evaluated in spleen after 24 hours. Target cell clearance is expressed as killing ratio relative to the control cells. (I) Tumor growth, (J) tumor clearance rates at day 40, and (K) mouse survival were assessed in the indicated 4 groups of BM chimeric mice (n = 11–12). (L–O) miR155 (bic RNA) or Arg2 mRNA were quantified by real-time PCR over a 48-hour time course in ex vivo WT or miR155–/– CD4+ (L and N) or CD8+ (M and O) T cells activated with αCD3ε and αCD28 antibodies (n = 6). (A–O) Results were pooled from 2 or 3 independent experiments. Data is represented as mean ± SEM throughout. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 (A, C, I, L–O: 2-way ANOVA) (E–G: 2-tailed Student’s t test) (B, D, K: log-rank Mantel-Cox test) (J: Fisher’s exact test).