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

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

  • Cell. 2024 Apr 25;187(9):2288-2304.e27. doi: 10.1016/j.cell.2024.03.011.
Tianyu Cao 1 Wenyao Zhang 1 Qi Wang 2 Chen Wang 2 Wanqi Ma 1 Cangang Zhang 3 Minghui Ge 4 Miaomiao Tian 1 Jia Yu 5 Anjun Jiao 3 Liang Wang 6 Manjiao Liu 4 Pei Wang 1 Zhiyu Guo 1 Yun Zhou 5 Shuyi Chen 1 Wen Yin 7 Jing Yi 7 Hao Guo 4 Hua Han 8 Baojun Zhang 3 Kaichun Wu 1 Daiming Fan 1 Xin Wang 9 Yongzhan Nie 10 Yuanyuan Lu 11 Xiaodi Zhao 12
Affiliations

Affiliations

  • 1 State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, National Clinical Research Center for Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
  • 2 State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, National Clinical Research Center for Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China; Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China; College of Life Sciences, Northwest University, Xi'an, Shaanxi 710069, China.
  • 3 Department of Pathogenic Microbiology and Immunology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China.
  • 4 Simcere Diagnostics Co., Ltd., Nanjing, Jiangsu 210042, China.
  • 5 Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China.
  • 6 Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
  • 7 Department of Blood Transfusion, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
  • 8 Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
  • 9 State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, National Clinical Research Center for Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China; Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China. Electronic address: wangx@fmmu.edu.cn.
  • 10 State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, National Clinical Research Center for Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China. Electronic address: yongznie@fmmu.edu.cn.
  • 11 State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, National Clinical Research Center for Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China. Electronic address: luyuandreamer@aliyun.com.
  • 12 State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, National Clinical Research Center for Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China. Electronic address: leedyzhao@fmmu.edu.cn.
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 and tumor progression. The taurine transporter SLC6A6 is correlated with aggressiveness and poor outcomes in multiple cancers. SLC6A6-mediated taurine uptake promotes the malignant behaviors of tumor cells but also increases the survival and effector function of 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-dependent manner. Increased ATF4 transactivates multiple immune checkpoint genes and induces T cell exhaustion. In gastric Cancer, we identify a chemotherapy-induced SP1-SLC6A6 regulatory axis. Our findings suggest that tumoral-SLC6A6-mediated taurine deficiency promotes immune evasion and that taurine supplementation reinvigorates exhausted CD8+ T cells and increases the efficacy of Cancer therapies.

Keywords

ATF4; ER stress; T cell exhaustion; chemoresistance; gastric cancer; immune checkpoint; solute carrier; taurine; transcription regulation; tumor recurrence and metastasis.

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