空军军医大学赵晓迪等研究人员合作发现，癌症SLC6A6介导的牛磺酸摄取可反式激活免疫检查点基因并诱导CD8⁺ T细胞衰竭。2024年4月1日，国际知名学术期刊《细胞》在线发表了这一成果。

研究人员报告了癌症相关的牛磺酸消耗会导致T细胞衰竭和肿瘤进展。牛磺酸转运体SLC6A6与多种癌症的侵袭性和不良预后有关。SLC6A6介导的牛磺酸摄取促进了肿瘤细胞的恶性行为，但也提高了CD8⁺ T细胞的存活率和效应功能。肿瘤细胞通过过量表达SLC6A6来竞争CD8⁺ T细胞对牛磺酸的摄取，从而诱导T细胞死亡和功能失调，进而助长肿瘤的发展。

从机理上讲，CD8⁺ T细胞缺乏牛磺酸会增加ER应激，以PERK-JAK1-STAT3信号依赖的方式促进ATF4转录。ATF4的增加可转录多个免疫检查点基因，并诱导T细胞衰竭。在胃癌中，研究人员发现了化疗诱导的SP1-SLC6A6调节轴。这些研究结果表明，肿瘤SLC6A6介导的牛磺酸缺乏会促进免疫逃避，而补充牛磺酸则能重振衰竭的CD8⁺ T细胞并提高癌症疗法的疗效。

据悉，牛磺酸可用于增强免疫力，但其对抗肿瘤免疫力的影响尚不清楚。

附：英文原文

Title: Cancer SLC6A6-mediated taurine uptake transactivates immune checkpoint genes and induces exhaustion in CD8+ T cells

Author: Tianyu Cao, Wenyao Zhang, Qi Wang, Chen Wang, Wanqi Ma, Cangang Zhang, Minghui Ge, Miaomiao Tian, Jia Yu, Anjun Jiao, Liang Wang, Manjiao Liu, Pei Wang, Zhiyu Guo, Yun Zhou, Shuyi Chen, Wen Yin, Jing Yi, Hao Guo, Hua Han, Baojun Zhang, Kaichun Wu, Daiming Fan, Xin Wang, Yongzhan Nie, Yuanyuan Lu, Xiaodi Zhao

Issue&Volume: 2024-04-01

Abstract: Taurine is used to bolster immunity, but its effects on antitumor immunity are unclear.Here, we report that cancer-related taurine consumption causes T cell exhaustion andtumor progression. The taurine transporter SLC6A6 is correlated with aggressivenessand poor outcomes in multiple cancers. SLC6A6-mediated taurine uptake promotes themalignant behaviors of tumor cells but also increases the survival and effector functionof CD8+ T cells. Tumor cells outcompete CD8+ T cells for taurine by overexpressing SLC6A6, which induces T cell death and malfunction,thereby fueling tumor progression. Mechanistically, taurine deficiency in CD8+ T cells increases ER stress, promoting ATF4 transcription in a PERK-JAK1-STAT3 signaling-dependentmanner. Increased ATF4 transactivates multiple immune checkpoint genes and inducesT cell exhaustion. In gastric cancer, we identify a chemotherapy-induced SP1-SLC6A6regulatory axis. Our findings suggest that tumoral-SLC6A6-mediated taurine deficiencypromotes immune evasion and that taurine supplementation reinvigorates exhausted CD8+ T cells and increases the efficacy of cancer therapies.

DOI: 10.1016/j.cell.2024.03.011

Source: https://www.cell.com/cell/abstract/S0092-8674(24)00303-9