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

Area of Science:

• Immunology
• Cancer Biology
• Cellular Metabolism

Background:

• Extracellular arginine depletion by arginase 1 (Arg1) is a known immunosuppressive mechanism.
• The intracellular roles of arginases, particularly within T cells, remain largely uncharacterized.
• Arginase 2 (Arg2) is the mitochondrial isoform expressed in T cells.

Purpose of the Study:

• To investigate the cell-autonomous functions of arginase 2 (Arg2) in CD8+ T cells.
• To determine if Arg2 regulates T cell activity and anti-tumor responses independently of extracellular arginine.
• To evaluate Arg2 as a potential therapeutic target in cancer immunotherapy.

Main Methods:

• Utilized germline Arg2 deletion and adoptive transfer of Arg2 knockout (Arg2-/-) CD8+ T cells in preclinical cancer models.
• Performed transcriptomic, proteomic, and high-dimensional flow cytometry analyses.
• Investigated the synergy between Arg2 deletion in CD8+ T cells and PD-1 blockade.
• Assessed the effect of pharmacologic arginase inhibition on ex vivo human T cell activation.

Main Results:

• Germline Arg2 deletion and transfer of Arg2-/- CD8+ T cells significantly reduced tumor growth.
• Arg2 deficiency enhanced CD8+ T cell activation, effector function, and persistence within tumors.
• Arg2 acts intrinsically within CD8+ T cells to modulate T cell activation, cytotoxicity, and memory formation, irrespective of extracellular arginine levels.
• Specific deletion of Arg2 in CD8+ T cells synergized with PD-1 blockade to improve tumor control and survival.
• Pharmacologic arginase inhibition accelerated ex vivo human T cell activation.

Conclusions:

• Mitochondrial Arginase 2 (Arg2) is a cell-intrinsic regulator of CD8+ T cell anti-tumor immunity.
• Targeting Arg2 within T cells represents a novel strategy to enhance cancer immunotherapy efficacy.
• Arg2 inhibition holds promise as a therapeutic approach for T cell-based cancer treatments, potentially synergizing with existing immunotherapies like PD-1 blockade.