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Tryptophan metabolism regulates anti-tumor immunity. The Slc7a5-Tryptophan pathway activates AhR to boost FasL, enhancing CTLs against tumors. This offers a new immunotherapy target.

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Area of Science:

  • Immunology
  • Cancer Biology
  • Metabolic Pathways

Background:

  • Tryptophan (Trp) metabolites are crucial for anti-tumor immunity and immunotherapy response.
  • The precise role of Trp in tumor-specific cytotoxic T lymphocytes (CTLs) within the tumor microenvironment remains unclear.

Purpose of the Study:

  • To elucidate the mechanism of Trp metabolism in tumor-activated CTLs and its impact on anti-tumor immunity.
  • To investigate the Slc7a5-Trp-AhR-FasL axis in CTL function and its therapeutic potential.

Main Methods:

  • Genome-wide metabolomics, RNA-sequencing, and ATAC-sequencing in co-cultured tumor-specific CTLs and tumor cells.
  • Pharmacological inhibition of Slc7a5 and genetic deficiency models in mice.
  • scRNA-sequencing, chromatin immunoprecipitation, and FasL blockade experiments.
  • Analysis of human cancer patient data correlating gene expression with immunotherapy response and survival.

Main Results:

  • Trp levels were elevated in tumor-activated CTLs, which upregulated Slc7a5 expression.
  • Slc7a5 inhibition reduced Trp uptake and CTL lytic activity.
  • T cell-specific Slc7a5 deficiency impaired anti-tumor immunity, increasing tumor growth and metastasis.
  • Slc7a5 deficiency decreased Aryl hydrocarbon receptor (AhR) activation and FasL expression in T cells.
  • AhR directly binds to the Faslg promoter.
  • FasL blockade exacerbated tumor progression.
  • In human cancers, AhR and FasL expression correlated, with FasL linked to pembrolizumab response and survival.

Conclusions:

  • The Slc7a5-Trp metabolic pathway is essential for activating AhR, which upregulates FasL in tumor-infiltrating T cells, thereby sustaining CTL anti-tumor immunity.
  • Targeting Slc7a5 to enhance T cell function presents a promising strategy for cancer immunotherapy, potentially improving CAR-T cell efficacy.