ReferenceID 3090
Tryptophan potentiates CD8+ T cells against cancer cells by TRIP12 tryptophanylation and surface PD-1 downregulation
J Immunother Cancer
BACKGROUND: Tryptophan catabolites suppress immunity. Therefore, blocking tryptophan catabolism with indoleamine 2,3-dioxygenase (IDO) inhibitors is pursued as an anticancer strategy. METHODS: The intracellular level of
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Record Fields
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- Reference Id
- 3090
- Evidence Id
- 19680
- Core Evidence Id
- 19680
- Source Reference Id
- 6178
- Herb2 Reference Id
- HBREF006975
- Subject Paper Key
- HBIN047282_34326168
- Pubmed Id
- 34326168
- Doi
- 10.1136/jitc-2021-002840
- Paper Title
- Tryptophan potentiates CD8+ T cells against cancer cells by TRIP12 tryptophanylation and surface PD-1 downregulation
- Paper Abstract
- BACKGROUND: Tryptophan catabolites suppress immunity. Therefore, blocking tryptophan catabolism with indoleamine 2,3-dioxygenase (IDO) inhibitors is pursued as an anticancer strategy. METHODS: The intracellular level of tryptophan and kynurenine was detected by mass spectrum analysis. The effect of tryptophan and IDO inhibitors on cell surface programmed cell death protein 1 (PD-1) level were measured by flow cytometry. A set of biochemical analyses were used to figure out the underlying mechanism. In vitro co-culture system, syngeneic mouse models, immunofluorescent staining, and flow cytometry analysis were employed to investigate the role of tryptophan and IDO inhibitor in regulating the cytotoxicity of CD8+ T cells. RESULTS: Here, we reported that IDO inhibitors activated CD8+ T cells also by accumulating tryptophan that downregulated PD-1. Tryptophan and IDO inhibitors administration, both increased intracellular tryptophan, and tryptophanyl-tRNA synthetase (WARS) overexpression decreased Jurkat and mice CD8+ T cell surface PD-1. Mechanistically, WARS tryptophanylated lysine 1136 of and activated E3 ligase TRIP12 to degrade NFATc1, a PD-1 transcription activator. SIRT1 de-tryptophanylated TRIP12 and reversed the effects of tryptophan and WARS on PD-1. Tryptophan or IDO inhibitors potentiated CD8+ T cells to induce apoptosis of co-cultured cancer cells, increased cancer-infiltrating CD8+ T cells and slowed down tumor growth of lung cancer in mice. CONCLUSIONS: Our results revealed the immune-activating efficacy of tryptophan, and suggested tryptophan supplemental may benefit IDO inhibitors and PD-1 blockade during anticancer treatments.
- Journal
- J Immunother Cancer
- Publish Year
- 2021
- Experiment Subject
- mouse; co-cultured cancer cells; jurkat
- Experiment Type
- Animal & Cell Experiment
- Phenotype Related
- Tumor; Cancer; Lung Cancer
- Paper Title Cn
- Paper Title En
- Tryptophan potentiates CD8+ T cells against cancer cells by TRIP12 tryptophanylation and surface PD-1 downregulation
- Bilingual Status
- semi_complete