Cancer SLC6A6-mediated taurine uptake impairs CD8+ T cell antitumor immunity by upregulating immune checkpoints [mouse RNA-Seq]

Taurine is a supplement used to bolster immunity, but how taurine affects antitumor immunity remains largely unknown. We report that SLC6A6-mediated uptake of taurine by gastric cancer (GC) cells results in T cell exhaustion and cancer progression. SLC6A6 was correlated with GC aggressiveness and poor outcomes, and taurine uptake increased GC proliferation, survival, and cell motility. Taurine significantly increased CD8+ T cell infiltration and cytotoxic effector expression in GC tumors. Mechanistically, taurine deprivation in CD8+ T cells increased ER stress and the unfolded protein response, resulting in AT4 transcription, which acts as a switch for T cell exhaustion. SLC6A6 was transactivated by SP1 in GC cells, with a strong correlation between SP1 and SLC6A6 in GC patients. The SP1-SLC6A6 axis was triggered by chemotherapy. Our findings reveal that SLC6A6-mediated taurine consumption impacts immune evasion and propose that taurine supplementation might reinvigorate CD8+ T cell response and enhance therapy efficacy. Single CD45+ immune cells were obtained from taurine-treated MFC tumors from 615 mice and compared to their counterparts in saline-treated tumors.

牛磺酸（Taurine）是一种用于增强机体免疫功能的膳食补充剂，但牛磺酸如何影响抗肿瘤免疫应答目前尚未完全阐明。本研究发现，胃癌（GC）细胞通过SLC6A6介导摄取牛磺酸，可诱导T细胞耗竭并促进肿瘤进展。SLC6A6的表达与胃癌的侵袭性及不良临床预后密切相关，而牛磺酸摄取可增强胃癌细胞的增殖、存活与迁移能力。牛磺酸可显著提升胃癌组织中CD8阳性T细胞（CD8+ T细胞）的浸润水平及细胞毒性效应分子的表达量。机制研究表明，CD8阳性T细胞内的牛磺酸缺乏会加剧内质网应激（ER stress）与未折叠蛋白反应（unfolded protein response），进而诱导AT4转录，该过程可作为T细胞耗竭的分子开关。胃癌细胞中，SLC6A6可被SP1转录激活，且胃癌患者组织中SP1与SLC6A6的表达水平呈显著正相关。化疗可触发SP1-SLC6A6信号轴的激活。本研究结果揭示，SLC6A6介导的牛磺酸消耗会影响肿瘤的免疫逃逸，并提出牛磺酸补充或可恢复CD8阳性T细胞的免疫应答功能，进而提升治疗效果。本研究从615只经牛磺酸处理的小鼠的MFC移植瘤组织中分离得到单个CD45阳性免疫细胞（CD45+ immune cells），并将其与生理盐水处理组小鼠肿瘤组织中的对应免疫细胞进行对比分析。