{"title":"TGF-β-p-STAT1-LAIR2轴对肝癌中耗尽的CD8+ T细胞具有“自救”作用。","authors":"Banglun Pan, Zengbin Wang, Yuxin Yao, Xiaoling Ke, Shuling Shen, Weihong Chen, Xiaoxia Zhang, Jiacheng Qiu, Xiaoxuan Wu, Nanhong Tang","doi":"10.1007/s13402-023-00830-9","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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<sup>+</sup> T cells in hepatocellular carcinoma (HCC) have not been clearly resolved.</p><p><strong>Methods: </strong>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<sup>+</sup> T cells.</p><p><strong>Results: </strong>Here, we demonstrated that the overall effect of TGF-β on CD8<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> T cells was improved by using TAK-981 to amplify \"self-rescue\" signal.</p><p><strong>Conclusion: </strong>Our study describes a \"self-rescue\" mechanism of CD8<sup>+</sup> T cells in HCC against exhaustion and the good effects from amplifying this signal.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1625-1644"},"PeriodicalIF":4.9000,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"2","resultStr":"{\"title\":\"TGF-β-p-STAT1-LAIR2 axis has a \\\"self-rescue\\\" role for exhausted CD8<sup>+</sup> T cells in hepatocellular carcinoma.\",\"authors\":\"Banglun Pan, Zengbin Wang, Yuxin Yao, Xiaoling Ke, Shuling Shen, Weihong Chen, Xiaoxia Zhang, Jiacheng Qiu, Xiaoxuan Wu, Nanhong Tang\",\"doi\":\"10.1007/s13402-023-00830-9\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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<sup>+</sup> T cells in hepatocellular carcinoma (HCC) have not been clearly resolved.</p><p><strong>Methods: </strong>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<sup>+</sup> T cells.</p><p><strong>Results: </strong>Here, we demonstrated that the overall effect of TGF-β on CD8<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> T cells was improved by using TAK-981 to amplify \\\"self-rescue\\\" signal.</p><p><strong>Conclusion: </strong>Our study describes a \\\"self-rescue\\\" mechanism of CD8<sup>+</sup> T cells in HCC against exhaustion and the good effects from amplifying this signal.</p>\",\"PeriodicalId\":49223,\"journal\":{\"name\":\"Cellular Oncology\",\"volume\":\" \",\"pages\":\"1625-1644\"},\"PeriodicalIF\":4.9000,\"publicationDate\":\"2023-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"2\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cellular Oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s13402-023-00830-9\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2023/5/24 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cellular Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s13402-023-00830-9","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/5/24 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
TGF-β-p-STAT1-LAIR2 axis has a "self-rescue" role for exhausted CD8+ T cells in hepatocellular carcinoma.
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.
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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