Oncometabolite d-2HG alters T cell metabolism to impair CD8⁺ T cell function

Area of Science:

• Metabolic reprogramming in cancer immunology
• Oncometabolite-mediated immune evasion

Background:

• Gain-of-function mutations in isocitrate dehydrogenase (IDH) lead to the production of the oncometabolite d-2-hydroxyglutarate (d-2HG) in cancers.
• While d-2HG's cell-intrinsic effects are known, its impact on immune cells is less understood.

Purpose of the Study:

• To investigate the nonautonomous roles of tumor-derived d-2HG on immune cells.
• To compare the effects of d-2HG and its enantiomer, l-2HG, on CD8+ T cells.

Main Methods:

• Comparative analysis of d-2HG and l-2HG effects on CD8+ T cells.
• Identification of molecular targets of d-2HG within T cells.
• Metabolic and functional assays on CD8+ T cells.
• Analysis of clinical samples from patients with IDH1-mutant gliomas.

Main Results:

• Tumor-derived d-2HG is taken up by CD8+ T cells, altering their metabolism and antitumor functions reversibly.
• Lactate dehydrogenase (LDH) was identified as a molecular target of d-2HG.
• d-2HG and LDH inhibition induce a metabolic program decreasing CD8+ T cell cytotoxicity and impairing interferon-gamma signaling.
• These findings were consistent with observations in human IDH1-mutant gliomas.

Conclusions:

• d-2HG exerts tumor cell-nonautonomous effects by impairing CD8+ T cell antitumor immunity.
• Targeting LDH may represent a therapeutic strategy in IDH-mutant cancers.
• Understanding d-2HG's immune effects provides insights into cancer progression and immune evasion.