Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China.
Cancer Center of Fujian Medical University, Fujian Medical University Union Hospital, Fuzhou, 350001, China.
Cell Oncol (Dordr). 2023 Dec;46(6):1625-1644. doi: 10.1007/s13402-023-00830-9. Epub 2023 May 24.
TGF-β is related to the function of T cells in the tumor microenvironment. However, the characteristics of TGF-β affecting the function of CD8 T cells in hepatocellular carcinoma (HCC) have not been clearly resolved.
In this study, flow cytometry, mass cytometry, immunohistochemistry, RNA-seq, single-cell RNA-seq, assay for transposase-accessible chromatin with high throughput sequencing, chromatin immunoprecipitation, and dual-luciferase reporter gene assay were used to study the regulatory effect and molecular mechanism of TGF-β on HCC infiltrating CD8 T cells.
Here, we demonstrated that the overall effect of TGF-β on CD8 T cells in HCC was to activate p-p38 to induce exhaustion, but it also initiated cell-intrinsic resistance mechanisms: 1) TGF-β upregulated the levels of p-STAT1 (S727) and promoted LAIR2 secretion; 2) the TGF-β-p-STAT1-LAIR2 axis relieved CD8 T cells from exhaustion, which we called "self-rescue"; 3) this "self-rescue" behavior showed time and dose limitations on TGF-β stimulation, which was easily masked by stronger inhibitory signals; 4) the function of CD8 T cells was improved by using TAK-981 to amplify "self-rescue" signal.
Our study describes a "self-rescue" mechanism of CD8 T cells in HCC against exhaustion and the good effects from amplifying this signal.
TGF-β 与肿瘤微环境中 T 细胞的功能有关。然而，TGF-β 影响肝细胞癌（HCC）中 CD8 T 细胞功能的特征尚未得到明确解决。
在这项研究中，使用流式细胞术、液质联用技术、免疫组织化学、RNA-seq、单细胞 RNA-seq、高通量测序的转座酶可及染色质分析、染色质免疫沉淀和双荧光素酶报告基因检测来研究 TGF-β 对 HCC 浸润 CD8 T 细胞的调节作用和分子机制。
在这里，我们证明了 TGF-β 对 HCC 中 CD8 T 细胞的总体影响是激活 p-p38 以诱导衰竭，但它也启动了细胞内在的抵抗机制：1）TGF-β 上调了 p-STAT1（S727）的水平并促进了 LAIR2 的分泌；2）TGF-β-p-STAT1-LAIR2 轴缓解了 CD8 T 细胞的衰竭，我们称之为“自我拯救”；3）这种“自我拯救”行为对 TGF-β 刺激具有时间和剂量限制，很容易被更强的抑制信号掩盖；4）通过使用 TAK-981 放大“自我拯救”信号来改善 CD8 T 细胞的功能。
我们的研究描述了 HCC 中 CD8 T 细胞对抗衰竭的“自我拯救”机制以及放大这种信号的良好效果。
