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  3. 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.
PMID: 38565142 DOI: 10.1016/j.cell.2024.03.011
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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