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
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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.
Products
Inhibitors & Agonists
Other Products