Xia Zhixiu, Ding Xiaoxu, Ji Chao, Zhou Dabo, Sun Xun, Liu Tiancong
Colorectal Tumor Surgery Ward, Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, P.R. China.
Department of Otorhinolaryngology-Head and Neck Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, P.R. China.
iScience. 2024 Jan 17;27(2):108957. doi: 10.1016/j.isci.2024.108957. eCollection 2024 Feb 16.
Competition for glucose may metabolically limit T cells during cancer progression. This study shows that culturing in the condition medium (CM) of NPC c6661 cells restricted glycolytic and immune activities of CD8 T cells. These cells also exhibited limited tumor-eliminating effects in mouse xenograft tumor models. Glucose supplementation restored glycolysis and immune activity of CD8 T cells and by rescuing the expression of E1A binding protein p300 (EP300). EP300 upregulated bromodomain PHD finger transcription factor (BPTF) expression by catalyzing H3K27ac modification, and BPTF further activated AT-rich interaction domain 1A (ARID1A) transcription. Either BPTF or ARID1A knockdown in CD8 T cells reduced their glycolytic activity, decreased the secretion of cytotoxic molecules, and blocked the tumor-killing function in mice. Overall, this study demonstrates that EP300 restores the glycolytic and anti-tumor activities of CD8 T cells in the glucose restriction condition in NPC through the BPTF/ARID1A axis.
在癌症进展过程中，对葡萄糖的竞争可能在代谢上限制T细胞。本研究表明，在鼻咽癌c6661细胞的条件培养基（CM）中培养会限制CD8 T细胞的糖酵解和免疫活性。这些细胞在小鼠异种移植肿瘤模型中也表现出有限的肿瘤消除作用。补充葡萄糖可恢复CD8 T细胞的糖酵解和免疫活性，并通过挽救E1A结合蛋白p300（EP300）的表达来实现。EP300通过催化H3K27ac修饰上调溴结构域PHD指转录因子（BPTF）的表达，而BPTF进一步激活富含AT的相互作用结构域1A（ARID1A）的转录。CD8 T细胞中BPTF或ARID1A的敲低均降低了它们的糖酵解活性，减少了细胞毒性分子的分泌，并阻断了小鼠体内的肿瘤杀伤功能。总体而言，本研究表明，EP300通过BPTF/ARID1A轴在鼻咽癌葡萄糖限制条件下恢复CD8 T细胞的糖酵解和抗肿瘤活性。
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