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 6

Arg2 deletion enhances the persistence of antitumor CD8+ T cell responses and increases differentiation into Tcm cells.

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Arg2 deletion enhances the persistence of antitumor CD8+ T cell respons...
(A) The scheme illustrates the experimental setting used in panels B–H. The approach was similar to that in Figure 5A, except that tumor-bearing mice were adoptively transferred with a 1:1 mix of naive WT and Arg2–/– cells (1 × 106 to 1.3 × 106 total cells). (B) The representative contour plots illustrate the approach used in C and D to use CD45.1 staining to discriminate between WT CD45.1+/+ and Arg2–/– CD45.1+/– CD8+ OT-I cells. (C and D) The graphs summarize the spatiotemporal distribution of adoptively transferred WT (C) or Arg2–/– (D) CD8+ OT-I cells during the course of the antitumor response (n = 10). (E) The graphs show the percentage of Arg2–/– cells within the total transferred OT-I cell populations found at the indicated time points in the TdLNs and tumors (n = 10). (F) The representative contour plots illustrate how viable and dead fractions were quantified 15 days after transfer within the cotransferred WT and Arg2–/– CD8+ OT-I cell populations in the TdLNs (top) and tumor infiltrates (bottom). (G and H) The graphs summarize the Arg2–/– versus WT CD8+ OT-I cell ratios found at different time points within the viable and dead cell fractions in tumors (G) or in TdLNs (H). (I and J) In the setting illustrated in Figure 5A, flow cytometry was used 8 days after transfer to quantify the frequencies of IFN-γ+ cells in WT and Arg2–/– OT-I cell populations (I) or the expression of PD-1 by WT and Arg2–/– OT-I cells (J) in TdLNs and tumor infiltrates. (K–M) WT CD45.1+/+ or Arg2–/– CD45.1+/– CD8+ OT-I cells were adoptively transferred into naive WT hosts, which were immunized with CpG-B and OVA257–264 24 hours later. Cell frequency (K), central/effector memory differentiation (L), and CCR7 (M) were analyzed by flow cytometry in OT-I cells found in spleen (Spl), draining (dLN), and nondraining lymph nodes (ndLN) 28 days after immunization. Violin plots (K, L, M) show the median and quartiles. (C–E and G–M) Results were pooled from 2 or 3 independent experiments. *P < 0.05, **P < 0.01, and ***P < 0.001 (G–M: 2-tailed Student’s t test) (E: 2-tailed Welch’s t tests)