Lu Chunwan, Liang Liyan, Wu Yanmin, Yang Yingcui, Poschel Dakota, Zhao Yang, Pei Lirong, Yu Miao, Zoccheddu Martina, Bombin Sergei, Ding Han-Fei, Shi Huidong, Liu Kebin
School of Life Sciences, Tianjin University, Tianjin, China.
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA, USA.
Oncogene. 2025 Aug 26. doi: 10.1038/s41388-025-03543-5.
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.
色氨酸（Trp）代谢产物已成为宿主肿瘤免疫和癌症患者对免疫治疗反应的关键调节因子。然而，肿瘤微环境中Trp在肿瘤激活的细胞毒性T淋巴细胞（CTLs）中的功能和潜在机制尚未完全明确。利用肿瘤特异性CTLs与表达同源抗原的肿瘤细胞组成的特定共培养系统，我们进行了全基因组代谢组学筛选，观察到肿瘤细胞激活的CTLs中Trp水平升高。并行的全基因组RNA测序和ATAC测序分析确定，肿瘤特异性CTLs通过转录激活Slc7a5表达来响应肿瘤细胞。对Slc7a5的药理学抑制降低了肿瘤激活的CTLs中Trp的摄取，并抑制了体外杀伤肿瘤细胞时CTL的裂解活性。仅T细胞中缺乏Slc7a5的小鼠肿瘤浸润T细胞水平降低，肿瘤生长和转移增加。单细胞RNA测序分析显示，Slc7a5缺乏导致肿瘤浸润T细胞中芳烃受体（AhR）途径的激活减少以及FasL表达受抑制。染色质免疫沉淀确定AhR与肿瘤浸润T细胞中的Faslg启动子结合。FasL阻断疗法促进荷瘤小鼠的肿瘤生长和转移。在人类癌症患者中，AhR表达与肿瘤浸润T细胞中的FasL表达相关。此外，FasL表达与患者对帕博利珠单抗的反应和生存时间相关。我们的研究发现确定了Slc7a5-Trp代谢途径激活AhR以上调肿瘤浸润T细胞中的FasL表达，从而维持CTL的抗肿瘤免疫。因此，靶向嵌合抗原受体T细胞（CAR-T细胞）上调Slc7a5以维持T细胞增殖和功能可能是癌症免疫治疗的一个有前景的方向。
