TGF-β-p-STAT1-LAIR2 axis has a "self-rescue" role for exhausted CD8+ T cells in hepatocellular carcinoma.

IF 4.9 2区 医学 Q2 CELL BIOLOGY Cellular Oncology Pub Date : 2023-12-01 Epub Date: 2023-05-24 DOI:10.1007/s13402-023-00830-9
Banglun Pan, Zengbin Wang, Yuxin Yao, Xiaoling Ke, Shuling Shen, Weihong Chen, Xiaoxia Zhang, Jiacheng Qiu, Xiaoxuan Wu, Nanhong Tang
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引用次数: 2

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: Our study describes a "self-rescue" mechanism of CD8+ T cells in HCC against exhaustion and the good effects from amplifying this signal.

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TGF-β-p-STAT1-LAIR2轴对肝癌中耗尽的CD8+ T细胞具有“自救”作用。
背景:TGF-β与肿瘤微环境中T细胞的功能有关。然而,TGF-β在肝细胞癌(HCC)中影响CD8+ T细胞功能的特点尚未明确解决。方法:本研究采用流式细胞术、大量细胞术、免疫组织化学、RNA-seq、单细胞RNA-seq、转座酶可及染色质高通量测序、染色质免疫沉淀、双荧光素酶报告基因检测等方法,研究TGF-β对HCC浸润CD8+ T细胞的调控作用及分子机制。结果:本研究表明,TGF-β对HCC中CD8+ T细胞的总体作用是激活p-p38诱导衰竭,但也启动了细胞内在抵抗机制:1)TGF-β上调p-STAT1 (S727)水平,促进LAIR2分泌;2) TGF-β-p-STAT1-LAIR2轴缓解了CD8+ T细胞的衰竭,我们称之为“自救”;3)这种“自救”行为对TGF-β刺激具有时间和剂量限制,容易被较强的抑制信号所掩盖;4) TAK-981可增强CD8+ T细胞的“自救”信号,提高其功能。结论:我们的研究描述了HCC中CD8+ T细胞对抗衰竭的“自我拯救”机制以及放大这一信号的良好效果。
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来源期刊
Cellular Oncology
Cellular Oncology ONCOLOGY-CELL BIOLOGY
CiteScore
10.30
自引率
1.50%
发文量
86
审稿时长
12 months
期刊介绍: The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.
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