SLC1A5-mediated kynurenine metabolism drives AHR-FANCD2 axis to remodel chromatin and induce T cell exhaustion in lung adenocarcinoma.

BACKGROUND: Kynurenine, a byproduct of tryptophan breakdown, is linked to immune suppression during cancer development. This study explores the involvement of the amino acid transporter solute carrier family 1 member 5 (SLC1A5) in kynurenine-mediated T cell exhaustion in LUAD and delves into its functional mechanism. METHODS: RNA-sequencing analysis was employed to identify transcriptome differences between T progenitor and terminal exhausted T cells (TPEX vs. TEX). The SLC1A5 expression was detected in T cells following L-kynurenine (L-ky) treatment. Mouse LUAD cells LLC were implanted into wild-type (WT), SLC1A5 knockout (SLC1A5(-/-)), SLC1A5(flox/flox) (SLC1A5(fl/fl)), or CD8⁺ T cell-specific SLC1A5 conditional knockout (SLC1A5(cko)) mice, followed by L-ky treatment, to examine the effect of SLC1A5(cko) on L-ky-mediated tumorigenesis and T cell exhaustion. Interacting proteins of AHR, a core transcription factor in the kynurenine pathway, were explored by liquid chromatography/mass spectrometry and bioinformatics. RESULTS: SLC1A5 is upregulated in TEX, and its expression in CD8(+) T cells was increased by L-ky treatment dose-dependently. The tumorigenic activity of LLC cells, under L-ky treatment stimulation, was suppressed in both SLC1A5(-/-) and SLC1A5(cko) mice, accompanied by increased T cell activity within tumors. CD8(+) T cells extracted from SLC1A5(cko) mice also showed reduced L-ky uptake and increased cytotoxicity in vitro. Mechanistically, AHR recruits the chromatin modifying enzyme FANCD2 to enhance SLC1A5 expression, promoting chromatin accessibility in T cells and cell exhaustion. CONCLUSION: This study suggests that SLC1A5 is upregulated in TEX, which modulates kynurenine metabolism and induces T cell exhaustion through the AHR-FANCD2 axis-mediated chromatin remodeling.