{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T13:26:54Z","timestamp":1792070814660,"version":"4.4.0"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2021,8,25]],"date-time":"2021-08-25T00:00:00Z","timestamp":1629849600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,8,25]],"date-time":"2021-08-25T00:00:00Z","timestamp":1629849600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,11]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>Recently, clinical trials of lenvatinib plus pembrolizumab in HCC have displayed an impressive objective response rate. This study aimed to clarify the mechanism for optimal patient selection.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>First, in patients with HCC, lenvatinib\u2010treated recurrent tumors had lower programmed death ligand 1 (PD\u2010L1) expression and regulatory T cell (Treg) infiltration compared with matched primary tumors. Consistently, in C57BL\/6 wild\u2010type mice receiving anti\u2013programmed cell death 1 (PD\u20101) therapy, PD\u2010L1 expression and Treg infiltration in s.c. tumors were reduced when adding lenvatinib to the scheme. Mechanistically, on the one hand, FGF receptor 4 (FGFR4) was the most pivotal target in PD\u2010L1 down\u2010regulation by lenvatinib <jats:italic toggle=\"yes\">in vitro<\/jats:italic>. Furthermore, lenvatinib reinforced the proteasomal degradation of PD\u2010L1 by blocking the FGFR4\u2013glycogen synthase kinase 3\u03b2 axis and rescued the sensitivity of interferon\u2010\u03b3\u2010pretreated HCC cells to T\u2010cell killing by targeting FGFR4. On the other hand, the level of IL\u20102 increased after anti\u2010PD\u20101 treatment, but IL\u20102\u2010mediated Treg differentiation was blocked by lenvatinib through targeting FGFR4 to restrain signal transducer and activator of transcription 5 (STAT5) phosphorylation. By regulating the variations in the number of Tregs and the tumor FGFR4 level in C57BL\/6\u2013forkhead box protein P3 (<jats:italic toggle=\"yes\">Foxp3DTR\n                                 <\/jats:italic>) mice, we found that high levels of FGFR4 and Treg infiltration sensitized tumors to the combination treatment. Finally, high levels of FGFR4 and Foxp3 conferred immune tolerance but better response to the combined therapy in patient cohorts.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Lenvatinib reduced tumor PD\u2010L1 level and Treg differentiation to improve anti\u2010PD\u20101 efficacy by blocking FGFR4. Levels of FGFR4 expression and Treg infiltration in tumor could serve as biomarkers for screening patients with HCC using lenvatinib plus anti\u2010PD\u20101 combination therapy.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.31921","type":"journal-article","created":{"date-parts":[[2021,5,26]],"date-time":"2021-05-26T04:37:00Z","timestamp":1622003820000},"page":"2544-2560","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":273,"title":["Lenvatinib Targets FGF Receptor 4 to Enhance Antitumor Immune Response of Anti\u2013Programmed Cell Death\u20101 in HCC"],"prefix":"10.1097","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0809-7196","authenticated-orcid":false,"given":"Chenhe","family":"Yi","sequence":"first","affiliation":[{"name":"Department of General Surgery,Huashan Hospital,Fudan University,Shanghai,PR China"},{"name":"Cancer Metastasis Institute,Fudan University,Shanghai,PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0333-4490","authenticated-orcid":false,"given":"Lirong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Digestive Diseases,Huashan Hospital,Fudan University,Shanghai,PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0661-1710","authenticated-orcid":false,"given":"Zhifei","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of General Surgery,Huashan Hospital,Fudan University,Shanghai,PR China"},{"name":"Cancer Metastasis Institute,Fudan University,Shanghai,PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases,Huashan Hospital,Fudan University,Shanghai,PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiqing","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of General Surgery,Huashan Hospital,Fudan University,Shanghai,PR China"},{"name":"Cancer Metastasis Institute,Fudan University,Shanghai,PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of General Surgery,Huashan Hospital,Fudan University,Shanghai,PR China"},{"name":"Cancer Metastasis Institute,Fudan University,Shanghai,PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of General Surgery,Huashan Hospital,Fudan University,Shanghai,PR China"},{"name":"Cancer Metastasis Institute,Fudan University,Shanghai,PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jubo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases,Huashan Hospital,Fudan University,Shanghai,PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenwei","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of General Surgery,Huashan Hospital,Fudan University,Shanghai,PR China"},{"name":"Cancer Metastasis Institute,Fudan University,Shanghai,PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huliang","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of General Surgery,Huashan Hospital,Fudan University,Shanghai,PR China"},{"name":"Cancer Metastasis Institute,Fudan University,Shanghai,PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4805-8239","authenticated-orcid":false,"given":"Lunxiu","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of General Surgery,Huashan Hospital,Fudan University,Shanghai,PR China"},{"name":"Cancer Metastasis Institute,Fudan University,Shanghai,PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of General Surgery,Huashan Hospital,Fudan University,Shanghai,PR China"},{"name":"Cancer Metastasis Institute,Fudan University,Shanghai,PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0952-9990","authenticated-orcid":false,"given":"Jinhong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of General Surgery,Huashan Hospital,Fudan University,Shanghai,PR China"},{"name":"Cancer Metastasis Institute,Fudan University,Shanghai,PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2021,8,25]]},"reference":[{"key":"hep31921-bib-0001-20250824","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1056\/NEJMra1713263","article-title":"Hepatocellular carcinoma","volume":"380","year":"2019","journal-title":"N Engl J Med"},{"key":"hep31921-bib-0002-20250824","doi-asserted-by":"crossref","first-page":"16018","DOI":"10.1038\/nrdp.2016.18","article-title":"Hepatocellular carcinoma","volume":"2","year":"2016","journal-title":"Nat Rev Dis Primers"},{"key":"hep31921-bib-0003-20250824","doi-asserted-by":"crossref","first-page":"2448","DOI":"10.1016\/S0140-6736(17)31044-9","article-title":"Immune oncology in hepatocellular carcinoma\u2014hype and hope","volume":"389","year":"2017","journal-title":"Lancet"},{"key":"hep31921-bib-0004-20250824","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1200\/JCO.19.01307","article-title":"Pembrolizumab as second\u2010line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE\u2010240: a randomized, double\u2010blind, phase III trial","volume":"38","year":"2020","journal-title":"J Clin Oncol"},{"key":"hep31921-bib-0005-20250824","doi-asserted-by":"crossref","first-page":"2492","DOI":"10.1016\/S0140-6736(17)31046-2","article-title":"Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open\u2010label, non\u2010comparative, phase 1\/2 dose escalation and expansion trial","volume":"389","year":"2017","journal-title":"Lancet"},{"key":"hep31921-bib-0006-20250824","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1158\/2159-8290.CD-15-0563","article-title":"Adaptive immune resistance: How cancer protects from immune attack","volume":"5","year":"2015","journal-title":"Cancer Discov"},{"key":"hep31921-bib-0007-20250824","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1182\/blood-2006-10-051482","article-title":"Plasma cells from multiple myeloma patients express B7\u2013H1 (PD\u2010L1) and increase expression after stimulation with IFN\u2010{gamma} and TLR ligands via a MyD88\u2010, TRAF6\u2010, and MEK\u2010dependent pathway","volume":"110","year":"2007","journal-title":"Blood"},{"key":"hep31921-bib-0008-20250824","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.cell.2014.12.033","article-title":"Molecular and genetic properties of tumors associated with local immune cytolytic activity","volume":"160","year":"2015","journal-title":"Cell"},{"key":"hep31921-bib-0009-20250824","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1038\/nri2785","article-title":"FOXP3+ regulatory T cells in the human immune system","volume":"10","year":"2010","journal-title":"Nat Rev Immunol"},{"key":"hep31921-bib-0010-20250824","doi-asserted-by":"crossref","first-page":"9999","DOI":"10.1073\/pnas.1822001116","article-title":"PD\u20101+ regulatory T cells amplified by PD\u20101 blockade promote hyperprogression of cancer","volume":"116","year":"2019","journal-title":"Proc Natl Acad Sci USA"},{"key":"hep31921-bib-0011-20250824","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.jhep.2019.09.010","article-title":"Molecular therapies for HCC: looking outside the box","volume":"72","year":"2020","journal-title":"J Hepatol"},{"key":"hep31921-bib-0012-20250824","doi-asserted-by":"crossref","first-page":"2960","DOI":"10.1200\/JCO.20.00808","article-title":"Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma","volume":"38","year":"2020","journal-title":"J Clin Oncol"},{"key":"hep31921-bib-0013-20250824","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.jhep.2018.03.019","article-title":"EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma","volume":"69","year":"2018","journal-title":"J Hepatol"},{"key":"hep31921-bib-0014-20250824","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1055\/s-0030-1247132","article-title":"Modified RECIST (mRECIST) assessment for hepatocellular carcinoma","volume":"30","year":"2010","journal-title":"Semin Liver Dis"},{"key":"hep31921-bib-0015-20250824","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1002\/hep.31412","article-title":"Intratumoral \u03b3\u03b4 T\u2010cell infiltrates, chemokine (C\u2010C Motif) ligand 4\/chemokine (C\u2010C Motif) ligand 5 protein expression and survival in patients with hepatocellular carcinoma","volume":"73","year":"2021","journal-title":"Hepatology"},{"key":"hep31921-bib-0016-20250824","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1053\/j.gastro.2020.03.074","article-title":"Hepatocellular carcinoma cells up\u2010regulate PVRL1, stabilizing PVR and inhibiting the cytotoxic T\u2010cell response via TIGIT to mediate tumor resistance to PD1 inhibitors in mice","volume":"159","year":"2020","journal-title":"Gastroenterology"},{"key":"hep31921-bib-0017-20250824","doi-asserted-by":"crossref","first-page":"12632","DOI":"10.1038\/ncomms12632","article-title":"Glycosylation and stabilization of programmed death ligand\u20101 suppresses T\u2010cell activity","volume":"7","year":"2016","journal-title":"Nat Commun"},{"key":"hep31921-bib-0018-20250824","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1146\/annurev-immunol-042617-053352","article-title":"Signaling and function of interleukin\u20102 in T lymphocytes","volume":"36","year":"2018","journal-title":"Annu Rev Immunol"},{"key":"hep31921-bib-0019-20250824","doi-asserted-by":"crossref","first-page":"1798","DOI":"10.1161\/CIRCULATIONAHA.118.036053","article-title":"C\u2010X\u2010C motif chemokine receptor 4 blockade promotes tissue repair after myocardial infarction by enhancing regulatory T cell mobilization and immune\u2010regulatory function","volume":"139","year":"2019","journal-title":"Circulation"},{"key":"hep31921-bib-0020-20250824","article-title":"IL\u201010 producing type 2 innate lymphoid cells prolong islet allograft survival","volume":"12","year":"2020","journal-title":"EMBO Mol Med"},{"key":"hep31921-bib-0021-20250824","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1002\/hep.25765","article-title":"Foxp3+ regulatory T cells protect the liver from immune damage and compromise virus control during acute experimental hepatitis B virus infection in mice","volume":"56","year":"2012","journal-title":"Hepatology"},{"key":"hep31921-bib-0022-20250824","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1038\/s41577-018-0009-3","article-title":"An early history of T cell\u2013mediated cytotoxicity","volume":"18","year":"2018","journal-title":"Nat Rev Immunol"},{"key":"hep31921-bib-0023-20250824","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1038\/nri3839","article-title":"Perforin and granzymes: function, dysfunction and human pathology","volume":"15","year":"2015","journal-title":"Nat Rev Immunol"},{"key":"hep31921-bib-0024-20250824","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.1053\/j.gastro.2019.01.252","article-title":"MET inhibitors promote liver tumor evasion of the immune response by stabilizing PDL1","volume":"156","year":"2019","journal-title":"Gastroenterology"},{"key":"hep31921-bib-0025-20250824","doi-asserted-by":"crossref","first-page":"4530","DOI":"10.1158\/1078-0432.CCR-18-2840","article-title":"Regorafenib promotes antitumor immunity via inhibiting PD\u2010L1 and IDO1 expression in melanoma","volume":"25","year":"2019","journal-title":"Clin Cancer Res"},{"key":"hep31921-bib-0026-20250824","doi-asserted-by":"crossref","first-page":"3630","DOI":"10.1158\/1078-0432.CCR-18-2548","article-title":"A novel mTORC1\/2 inhibitor (MTI\u201031) inhibits tumor growth, epithelial\u2013mesenchymal transition, metastases, and improves antitumor immunity in preclinical models of lung cancer","volume":"25","year":"2019","journal-title":"Clin Cancer Res"},{"key":"hep31921-bib-0027-20250824","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1136\/gutjnl-2018-316510","article-title":"Multidimensional analyses reveal distinct immune microenvironment in hepatitis B virus\u2013related hepatocellular carcinoma","volume":"68","year":"2019","journal-title":"Gut"},{"key":"hep31921-bib-0028-20250824","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1038\/s41590-020-0769-3","article-title":"The PD\u20101 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD\u20101 blockade therapies","volume":"21","year":"2020","journal-title":"Nat Immunol"},{"key":"hep31921-bib-0029-20250824","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/s41467-019-13826-7","article-title":"Siah2 control of T\u2010regulatory cells limits anti\u2010tumor immunity","volume":"11","year":"2020","journal-title":"Nat Commun"},{"key":"hep31921-bib-0030-20250824","article-title":"Regulatory T cell control of systemic immunity and immunotherapy response in liver metastasis","volume":"5","year":"2020","journal-title":"Sci Immunol"},{"key":"hep31921-bib-0031-20250824","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/s41586-019-1215-2","article-title":"Targeting the CBM complex causes T(reg) cells to prime tumours for immune checkpoint therapy","volume":"570","year":"2019","journal-title":"Nature"},{"key":"hep31921-bib-0032-20250824","doi-asserted-by":"crossref","first-page":"3993","DOI":"10.1111\/cas.13806","article-title":"Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1\u20106 hepatocellular carcinoma model","volume":"109","year":"2018","journal-title":"Cancer Sci"},{"key":"hep31921-bib-0033-20250824","article-title":"Lenvatinib plus anti\u2010PD\u20101 antibody combination treatment activates CD8+ T cells through reduction of tumor\u2010associated macrophage and activation of the interferon pathway","volume":"14","year":"2019","journal-title":"PLoS One"},{"key":"hep31921-bib-0034-20250824","first-page":"1382","article-title":"Lenvatinib promotes antitumor immunity by enhancing the tumor infiltration and activation of NK cells","volume":"9","year":"2019","journal-title":"Am J Cancer Res"},{"key":"hep31921-bib-0035-20250824","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/S0168-8278(02)00360-4","article-title":"Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy","volume":"38","year":"2003","journal-title":"J Hepatol"},{"key":"hep31921-bib-0036-20250824","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1016\/j.jhep.2009.07.009","article-title":"Risk factors for early and late recurrence in hepatitis B\u2013related hepatocellular carcinoma","volume":"51","year":"2009","journal-title":"J Hepatol"},{"key":"hep31921-bib-0037-20250824","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1016\/S1470-2045(20)30336-3","article-title":"Lenvatinib and pembrolizumab in advanced gastric cancer","volume":"21","year":"2020","journal-title":"Lancet Oncol"},{"key":"hep31921-bib-0038-20250824","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1016\/j.cell.2010.06.011","article-title":"Cell signaling by receptor tyrosine kinases","volume":"141","year":"2010","journal-title":"Cell"},{"key":"hep31921-bib-0039-20250824","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/S1535-6108(02)00076-4","article-title":"EGF receptor activation by heterologous mechanisms","volume":"1","year":"2002","journal-title":"Cancer Cell"},{"key":"hep31921-bib-0040-20250824","article-title":"Revisiting IL\u20102: biology and therapeutic prospects","volume":"3","year":"2018","journal-title":"Sci Immunol"},{"key":"hep31921-bib-0041-20250824","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1016\/j.immuni.2018.10.010","article-title":"Hippo kinases Mst1 and Mst2 sense and amplify IL\u20102R\u2010STAT5 signaling in regulatory T cells to establish stable regulatory activity","volume":"49","year":"2018","journal-title":"Immunity"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hep.31921","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/hep.31921","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/10.1002\/hep.31921","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,24]],"date-time":"2025-08-24T23:09:23Z","timestamp":1756076963000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1002\/hep.31921"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,25]]},"references-count":41,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2021]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.31921","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,25]]},"assertion":[{"value":"2020-12-05","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-05-07","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}