Tryptophan potentiates CD8+ T cells against cancer cells by TRIP12 tryptophanylation and surface PD-1 downregulation

Rui Qin, Chen Zhao, Chen-Ji Wang, Wei Xu, Jian-Yuan Zhao, Yan Lin, Yi-Yuan Yuan, Peng-Cheng Lin, Yao Li, Shimin Zhao, Yan Huang
2021 Journal for ImmunoTherapy of Cancer  
BackgroundTryptophan catabolites suppress immunity. Therefore, blocking tryptophan catabolism with indoleamine 2,3-dioxygenase (IDO) inhibitors is pursued as an anticancer strategy.MethodsThe 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.
more » ... n 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.ResultsHere, 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.ConclusionsOur results revealed the immune-activating efficacy of tryptophan, and suggested tryptophan supplemental may benefit IDO inhibitors and PD-1 blockade during anticancer treatments.
doi:10.1136/jitc-2021-002840 pmid:34326168 pmcid:PMC8323461 fatcat:arwprchwlnfddg5xw276yof5vq