{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T17:48:49Z","timestamp":1789494529301,"version":"build-2803163510"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,13]],"date-time":"2023-03-13T00:00:00Z","timestamp":1678665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100018625","name":"Science and Technology Innovation Plan Of Shanghai Science and Technology Commission","doi-asserted-by":"publisher","award":["8167030430, 81902366, 19YF1429000"],"award-info":[{"award-number":["8167030430, 81902366, 19YF1429000"]}],"id":[{"id":"10.13039\/501100018625","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background and aims<\/jats:title><jats:p>The key role of tissue-resident memory T (T<jats:sub>RM<\/jats:sub>) cells in the immune regulation of hepatocellular carcinoma (HCC) has been investigated and reported, but the regulatory mechanism of tumor microenvironment on T<jats:sub>RM<\/jats:sub> cells is still unclear. Lymphocyte activating gene 3 (LAG-3) is a promising next-generation immune checkpoint that is continuously expressed due to persistent antigen exposure in the tumor microenvironment. Fibrinogen-like protein 1 (FGL1) is a classical ligand of LAG-3 and can promote T cell exhaustion in tumors. Here, we excavated the effect of FGL1-LAG3 regulatory axis on T<jats:sub>RM<\/jats:sub> cells in HCC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The function and phenotype of intrahepatic CD8<jats:sup>+<\/jats:sup> T<jats:sub>RM<\/jats:sub> cells in 35 HCC patients were analyzed using multicolor flow cytometry. Using a tissue microarray of 80 HCC patients, we performed the prognosis analysis. Moreover, we investigated the suppressive effect of FGL1 on CD8<jats:sup>+<\/jats:sup> T<jats:sub>RM<\/jats:sub> cells both in <jats:italic>in vitro<\/jats:italic> induction model and <jats:italic>in vivo<\/jats:italic> orthotopic HCC mouse model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>There was an increase in LAG3 expression in CD8<jats:sup>+<\/jats:sup> T<jats:sub>RM<\/jats:sub> cells in end-stage HCC; moreover, FGL1 levels were negatively correlated with CD103 expression and related to poor outcomes in HCC. Patients with high CD8<jats:sup>+<\/jats:sup> T<jats:sub>RM<\/jats:sub> cell proportions have better outcomes, and FGL1-LAG3 binding could lead to the exhaustion of CD8<jats:sup>+<\/jats:sup> T<jats:sub>RM<\/jats:sub> cells in tumors, indicating its potential as a target for immune checkpoint therapy of HCC. Increased FGL1 expression in HCC may result in CD8<jats:sup>+<\/jats:sup> T<jats:sub>RM<\/jats:sub> cell exhaustion, causing tumor immune escape.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We identified CD8<jats:sup>+<\/jats:sup>T<jats:sub>RM<\/jats:sub> cells as a potential immunotherapeutic target and reported the effect of FGL1-LAG3 binding on CD8<jats:sup>+<\/jats:sup> T<jats:sub>RM<\/jats:sub> cell function in HCC.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1112672","type":"journal-article","created":{"date-parts":[[2023,3,13]],"date-time":"2023-03-13T05:03:00Z","timestamp":1678683780000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["Fibrinogen-like protein 1 promotes liver-resident memory T-cell exhaustion in hepatocellular carcinoma"],"prefix":"10.3389","volume":"14","author":[{"given":"Changjie","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiwei","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yudong","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingyuan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruilin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiyu","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenchen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengrui","family":"You","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianjun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaosong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,3,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA: Cancer J For Clin"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-0049","article-title":"Emerging opportunities and challenges in cancer immunotherapy","volume":"22","author":"Whiteside","year":"2016","journal-title":"Clin Cancer Res"},{"key":"B3","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1186\/s13045-021-01161-8","article-title":"Fibrinogen-like protein 1 (FGL1): The next immune checkpoint target","volume":"14","author":"Qian","year":"2021","journal-title":"J Hematol Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2015.35","article-title":"Development of immuno-oncology drugs - from CTLA4 to PD1 to the next generations","volume":"15","author":"Hoos","year":"2016","journal-title":"Nat Rev Drug Discov"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1021\/acs.molpharmaceut.8b00371","article-title":"Preclinical study of a fully human anti-PD-L1 antibody as a theranostic agent for cancer immunotherapy","volume":"15","author":"Xu","year":"2018","journal-title":"Mol Pharm"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2019.06.002","article-title":"Tissue-resident memory T cells in cancer immunosurveillance","volume":"40","author":"Park","year":"2019","journal-title":"Trends In Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3775","article-title":"Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer","volume":"18","author":"Ganesan","year":"2017","journal-title":"Nat Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-018-0114-2","article-title":"Tissue-resident memory T cells at the center of immunity to solid tumors","volume":"19","author":"Amsen","year":"2018","journal-title":"Nat Immunol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"4474","DOI":"10.1038\/s41467-021-24734-0","article-title":"CD8 tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells","volume":"12","author":"Koda","year":"2021","journal-title":"Nat Commun"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-0732","article-title":"CD103 and intratumoral immune response in breast cancer","volume":"22","author":"Wang","year":"2016","journal-title":"Clin Cancer Res"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-13-1877","article-title":"Tumor-infiltrating lymphocytes expressing the tissue resident memory marker CD103 are associated with increased survival in high-grade serous ovarian cancer","volume":"20","author":"Webb","year":"2014","journal-title":"Clin Cancer Res"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ejca.2016.02.026","article-title":"CD103 defines intraepithelial CD8+ PD1+ tumour-infiltrating lymphocytes of prognostic significance in endometrial adenocarcinoma","volume":"60","author":"Workel","year":"2016","journal-title":"Eur J Cancer (Oxford Engl 1990)."},{"key":"B13","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1016\/j.jhep.2022.02.032","article-title":"T-Cell exhaustion and residency dynamics inform clinical outcomes in hepatocellular carcinoma","volume":"77","author":"Barsch","year":"2022","journal-title":"J Hepatol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"2918","DOI":"10.1016\/j.cell.2022.06.018","article-title":"Tissue-resident memory and circulating T cells are early responders to pre-surgical cancer immunotherapy","volume":"185","author":"Luoma","year":"2022","journal-title":"Cell"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830241246","article-title":"Lymphocyte-activation gene 3\/major histocompatibility complex class II interaction modulates the antigenic response of CD4+ T lymphocytes","volume":"24","author":"Huard","year":"1994","journal-title":"Eur J Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.10.5392","article-title":"Cutting edge: Molecular analysis of the negative regulatory function of lymphocyte activation gene-3","volume":"169","author":"Workman","year":"2002","journal-title":"J Immunol (Baltimore Md 1950)."},{"key":"B17","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1111\/imr.12519","article-title":"LAG3 (CD223) as a cancer immunotherapy target","volume":"276","author":"Andrews","year":"2017","journal-title":"Immunol Rev"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0206-z","article-title":"Induction and transcriptional regulation of the co-inhibitory gene module in T cells","volume":"558","author":"Chihara","year":"2018","journal-title":"Nature"},{"key":"B19","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1084\/jem.20160485","article-title":"The EGR2 targets LAG-3 and 4-1BB describe and regulate dysfunctional antigen-specific CD8+ T cells in the tumor microenvironment","volume":"214","author":"Williams","year":"2017","journal-title":"J Exp Med"},{"key":"B20","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1093\/annonc\/mdx686","article-title":"Mechanistic overview of immune checkpoints to support the rational design of their combinations in cancer immunotherapy","volume":"29","author":"Rotte","year":"2018","journal-title":"Ann Oncol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00827-19","article-title":"Blockade of PD-1 and LAG-3 immune checkpoints combined with vaccination restores the function of antiviral tissue-resident CD8(+) TRM cells and reduces ocular herpes simplex infection and disease in HLA transgenic rabbits","volume":"93","author":"Roy","year":"2019","journal-title":"J Virol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1993.1678","article-title":"Molecular cloning and initial characterization of a novel fibrinogen-related gene, HFREP-1","volume":"193","author":"Yamamoto","year":"1993","journal-title":"Biochem Biophys Res Commun"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2008.171124","article-title":"Recombinant human hepassocin stimulates proliferation of hepatocytes in vivo and improves survival in rats with fulminant hepatic failure","volume":"59","author":"Li","year":"2010","journal-title":"Gut"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.11.010","article-title":"Fibrinogen-like protein 1 is a major immune inhibitory ligand of LAG-3","volume":"176","author":"Wang","year":"2019","journal-title":"Cell"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2020.106632","article-title":"Isolation and purification of immune cells from the liver","volume":"85","author":"Shi","year":"2020","journal-title":"Int Immunopharmacol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20162115","article-title":"IL-2 tissue-resident T cells in the human liver: Sentinels for hepatotropic infection","volume":"214","author":"Pallett","year":"2017","journal-title":"J Exp Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31739","article-title":"The clinical significance of hepatic CD69(+) CD103(+) CD8(+) resident memory T cells in autoimmune hepatitis","volume":"74","author":"You","year":"2021","journal-title":"Hepatology"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-18-0679","article-title":"CD3-bispecific antibody therapy turns solid tumors into inflammatory sites but does not install protective memory","volume":"18","author":"Benonisson","year":"2019","journal-title":"Mol Cancer Ther"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-20-1028","article-title":"NEIL3 prevents senescence in hepatocellular carcinoma by repairing oxidative lesions at telomeres during mitosis","volume":"81","author":"Zhao","year":"2021","journal-title":"Cancer Res"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21804","article-title":"Efficacy of a novel histone deacetylase inhibitor in murine models of hepatocellular carcinoma","volume":"46","author":"Lu","year":"2007","journal-title":"Hepatol (Baltimore Md)"},{"key":"B31","doi-asserted-by":"publisher","first-page":"989","DOI":"10.1016\/j.immuni.2016.05.001","article-title":"Lag-3, Tim-3, and TIGIT: Co-inhibitory receptors with specialized functions in immune regulation","volume":"44","author":"Anderson","year":"2016","journal-title":"Immunity"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.128633","article-title":"Combination of PD-L1 and PVR determines sensitivity to PD-1 blockade","volume":"5","author":"Lee","year":"2020","journal-title":"JCI Insight"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-17-0307","article-title":"TIMER: A web server for comprehensive analysis of tumor-infiltrating immune cells","volume":"77","author":"Li","year":"2017","journal-title":"Cancer Res"},{"key":"B34","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1186\/s13059-016-1028-7","article-title":"Comprehensive analyses of tumor immunity: Implications for cancer immunotherapy","volume":"17","author":"Li","year":"2016","journal-title":"Genome Biol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-019-00744-5","article-title":"CD8 T cell exhaustion","volume":"41","author":"Kurachi","year":"2019","journal-title":"Semin In Immunopathol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1186\/s12967-020-02469-8","article-title":"Expression and clinical significance of LAG-3, FGL1, PD-L1 and CD8(+)T cells in hepatocellular carcinoma using multiplex quantitative analysis","volume":"18","author":"Guo","year":"2020","journal-title":"J Transl Med"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.3151","article-title":"Oxysophocarpine suppresses hepatocellular carcinoma growth and sensitizes the therapeutic blockade of anti-Lag-3 via reducing FGL1 expression","volume":"9","author":"Wang","year":"2020","journal-title":"Cancer Med"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.11.008","article-title":"T-Box transcription factors combine with the cytokines TGF-beta and IL-15 to control tissue-resident memory T cell fate","volume":"43","author":"Mackay","year":"2015","journal-title":"Immunity"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abg3533","article-title":"Hobit identifies tissue-resident memory T cell precursors that are regulated by eomes","volume":"6","author":"Parga-Vidal L","year":"2021","journal-title":"Sci Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1112672\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,13]],"date-time":"2023-03-13T05:03:07Z","timestamp":1678683787000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1112672\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,13]]},"references-count":39,"alternative-id":["10.3389\/fimmu.2023.1112672"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1112672","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,13]]},"article-number":"1112672"}}