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<p>Tryptophan (Trp) metabolites have emerged as key regulators of host tumor immunity and cancer patient response to immunotherapy. However, the function of and mechanism underlying Trp in tumor-activated CTLs in the tumor microenvironment are incompletely understood. Using a defined co-culture system of tumor-specific CTLs and cognate antigen-expressing tumor cells, we performed a genome-wide metabolomics screening and observed that Trp level is elevated in the tumor cell-activated CTLs. Parallel genome-wide RNA-Sequencing and ATAC-Sequencing analysis determined that tumor-specific CTLs respond to tumor cells by transcriptionally activating Slc7a5 expression. Pharmacological inhibition of Slc7a5 decreased Trp uptake in tumor-activated CTLs and suppressed CTL lytic activity in killing tumor cells in vitro. Mice with Slc7a5 deficiency only in T cells exhibited diminished level of tumor-infiltrating T cells and increased tumor growth and metastasis. scRNA-sequencing analysis revealed that Slc7a5 deficiency resulted in decreased activation of the aryl hydrocarbon receptor (AhR) pathway and repressed FasL expression in tumor-infiltrating T cells. Chromatin immunoprecipitation determined that AhR binds to <i>Faslg</i> promoter in tumor-infiltrating T cells. FasL blockade therapy promotes tumor growth and metastasis in tumor-bearing mice. In human cancer patients, AhR expression correlates with FasL expression in tumor-infiltrating T cells. Furthermore, FasL expression is correlated with patient response to pembrolizumab and survival time. Our finding determines that the Slc7a5-Trp metabolic pathway activates AhR to up-regulate FasL expression in tumor-infiltrating T cells to sustain CTL anti-tumor immunity. Targeting CAR-T cells to up-regulate Slc7a5 to maintain T cell proliferation and function therefore could be a promising direction in cancer immunotherapy.</p>

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Slc7a5 promotes T cell anti-tumor immunity through sustaining cytotoxic T lymphocyte effector function

  • 期刊论文

  • 发表日期：

    2025年8月26日

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  • Chunwan Lu,
  • Liyan Liang,
  • Yanmin Wu,
  • Yingcui Yang,
  • Dakota Poschel,
  • Yang Zhao,
  • Lirong Pei,
  • Miao Yu,
  • Martina Zoccheddu,
  • Sergei Bombin,
  • Han-Fei Ding,
  • Huidong Shi,
  • Kebin Liu

摘要

Tryptophan (Trp) metabolites have emerged as key regulators of host tumor immunity and cancer patient response to immunotherapy. However, the function of and mechanism underlying Trp in tumor-activated CTLs in the tumor microenvironment are incompletely understood. Using a defined co-culture system of tumor-specific CTLs and cognate antigen-expressing tumor cells, we performed a genome-wide metabolomics screening and observed that Trp level is elevated in the tumor cell-activated CTLs. Parallel genome-wide RNA-Sequencing and ATAC-Sequencing analysis determined that tumor-specific CTLs respond to tumor cells by transcriptionally activating Slc7a5 expression. Pharmacological inhibition of Slc7a5 decreased Trp uptake in tumor-activated CTLs and suppressed CTL lytic activity in killing tumor cells in vitro. Mice with Slc7a5 deficiency only in T cells exhibited diminished level of tumor-infiltrating T cells and increased tumor growth and metastasis. scRNA-sequencing analysis revealed that Slc7a5 deficiency resulted in decreased activation of the aryl hydrocarbon receptor (AhR) pathway and repressed FasL expression in tumor-infiltrating T cells. Chromatin immunoprecipitation determined that AhR binds to Faslg promoter in tumor-infiltrating T cells. FasL blockade therapy promotes tumor growth and metastasis in tumor-bearing mice. In human cancer patients, AhR expression correlates with FasL expression in tumor-infiltrating T cells. Furthermore, FasL expression is correlated with patient response to pembrolizumab and survival time. Our finding determines that the Slc7a5-Trp metabolic pathway activates AhR to up-regulate FasL expression in tumor-infiltrating T cells to sustain CTL anti-tumor immunity. Targeting CAR-T cells to up-regulate Slc7a5 to maintain T cell proliferation and function therefore could be a promising direction in cancer immunotherapy.