{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:58:41Z","timestamp":1790834321701,"version":"4.1.0"},"reference-count":39,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2019,3,5]],"date-time":"2019-03-05T00:00:00Z","timestamp":1551744000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2019,3,5]],"date-time":"2019-03-05T00:00:00Z","timestamp":1551744000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2019,7]]},"abstract":"<jats:p>\n                    Immune checkpoint blockade has become a promising therapeutic approach to reverse immune cell exhaustion. Coinhibitory CD96 and T\u2010cell immunoglobulin and ITIM domain (TIGIT), together with costimulatory CD226, bind to common ligand CD155. The balancing between three receptors fine\u2010tunes immune responses against tumors. In this study, we investigated the expression of CD96, TIGIT, and CD226 in 55 fresh human hepatocellular carcinoma (HCC) samples, 236 paraffin\u2010embedded HCC samples, and 20 normal human livers. The cumulative percentage, absolute count, and mean fluorescence intensity (MFI) of CD96\n                    <jats:sup>+<\/jats:sup>\n                    NK cells are significantly increased in the intratumoral tissues of HCC and break the balance between three receptors. Human CD96\n                    <jats:sup>+<\/jats:sup>\n                    NK cells are functionally exhausted with impaired interferon\u2010gamma (IFN\u2010\u03b3) and tumor necrosis factor\u2010alpha (TNF\u2010\u03b1) production, high gene expression of interleukin (IL)\u201010 and transforming growth factor\u2010beta 1 (TGF\u2010\u03b21), and low gene expression of T\u2010bet, IL\u201015, perforin, and granzyme B. In addition, blocking CD96\u2010CD155 interaction specifically increases lysis of HepG2 cells by NK cells. HCC patients with a high level of CD96 or CD155 expression within tumor are strongly associated with deteriorating disease condition and shorter disease\u2010free survival (DFS) and overall survival times. Patients with a higher cumulative percentage of CD96\n                    <jats:sup>+<\/jats:sup>\n                    NK cells within tumor also exhibit shorter DFS. High plasma level of TGF\u2010\u03b21 in HCC patients up\u2010regulates CD96 expression and dynamically shifts the balance between CD96, TIGIT, and CD226 in NK cells. Blocking TGF\u2010\u03b21 specifically restores normal CD96 expression and reverses the dysfunction of NK cells.\n                    <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic>\n                    These findings indicate that human intratumoral CD96\n                    <jats:sup>+<\/jats:sup>\n                    NK cells are functionally exhausted and patients with higher intratumoral CD96 expression exhibit poorer clinical outcomes. Blocking CD96\u2010CD155 interaction or TGF\u2010\u03b21 restores NK cell immunity against tumors by reversing NK cell exhaustion, suggesting a possible therapeutic role of CD96 in fighting liver cancer.\n                  <\/jats:p>","DOI":"10.1002\/hep.30347","type":"journal-article","created":{"date-parts":[[2018,11,9]],"date-time":"2018-11-09T02:04:21Z","timestamp":1541729061000},"page":"168-183","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":273,"title":["Human CD96 Correlates to Natural Killer Cell Exhaustion and Predicts the Prognosis of Human Hepatocellular Carcinoma"],"prefix":"10.1097","volume":"70","author":[{"given":"Haoyu","family":"Sun","sequence":"first","affiliation":[{"name":"Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences,University of Science and Technology of 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University,Urumqi,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renyong","family":"Lin","sequence":"additional","affiliation":[{"name":"Xinjiang Key Laboratory of Echinococcosis,Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University,Urumqi,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meijuan","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory,First Affiliated Hospital of Anhui Medical University,Hefei,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Qu","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences,University of Science and Technology of China,Hefei,China"},{"name":"Institute of Immunology,University of Science and Technology of China,Hefei,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences,University of Science and Technology of China,Hefei,China"},{"name":"Institute of Immunology,University of Science and Technology of China,Hefei,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiming","family":"Wei","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences,University of Science and Technology of China,Hefei,China"},{"name":"Institute of Immunology,University of Science and Technology of China,Hefei,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weihua","family":"Xiao","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences,University of Science and Technology of China,Hefei,China"},{"name":"Institute of Immunology,University of Science and Technology of China,Hefei,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Sun","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences,University of Science and Technology of China,Hefei,China"},{"name":"Institute of Immunology,University of Science and Technology of China,Hefei,China"},{"name":"Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine,Zhejiang University,Hangzhou,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhigang","family":"Tian","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences,University of Science and Technology of China,Hefei,China"},{"name":"Institute of Immunology,University of Science and Technology of China,Hefei,China"},{"name":"Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine,Zhejiang 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