<br>癌症 SLC6A6 介导的牛磺酸摄取反式激活免疫检查点基因并诱导 CD8+ T 细胞耗竭,Cell

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癌症 SLC6A6 介导的牛磺酸摄取反式激活免疫检查点基因并诱导 CD8+ T 细胞耗竭
Cell ( IF 45.5 ) Pub Date : 2024-04-01 , 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 ₁ , Yuanyuan Lu ₁ , Xiaodi Zhao ₁

Affiliation

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.
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.
Department of Pathogenic Microbiology and Immunology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China.
Simcere Diagnostics Co., Ltd., Nanjing, Jiangsu 210042, China.
Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China.
Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
Department of Blood Transfusion, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
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.

牛磺酸用于增强免疫力，但其对抗肿瘤免疫力的影响尚不清楚。在此，我们报告与癌症相关的牛磺酸消耗会导致 T 细胞耗竭和肿瘤进展。牛磺酸转运蛋白 SLC6A6 与多种癌症的侵袭性和不良结果相关。 SLC6A6介导的牛磺酸摄取促进肿瘤细胞的恶性行为，但也增加CD8 T细胞的存活和效应功能。肿瘤细胞通过过度表达 SLC6A6 来争夺牛磺酸，从而诱导 T 细胞死亡和功能障碍，从而促进肿瘤进展。从机制上讲，CD8 T 细胞中的牛磺酸缺乏会增加 ER 应激，以 PERK-JAK1-STAT3 信号依赖的方式促进 ATF4 转录。 ATF4 增加会反式激活多个免疫检查点基因并诱导 T 细胞耗竭。在胃癌中，我们确定了化疗诱导的 SP1-SLC6A6 调节轴。我们的研究结果表明，肿瘤 SLC6A6 介导的牛磺酸缺乏会促进免疫逃避，而补充牛磺酸可以重振耗尽的 CD8 T 细胞并提高癌症治疗的功效。

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更新日期：2024-04-01

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