{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T13:38:42Z","timestamp":1770730722842,"version":"3.49.0"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T00:00:00Z","timestamp":1743379200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Purpose<\/jats:title><jats:p>This study aims to investigate the status of natural killer (NK) cells and the role of T-cell immunoreceptor with Ig and ITIM domains (TIGIT)-mediated regulation in diffuse large B-cell lymphoma (DLBCL).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Peripheral blood samples from 30 newly diagnosed DLBCL patients and 25 healthy controls were collected. Multiparametric flow cytometry was used to analyze the expression levels of TIGIT and its family molecules (CD226 and CD96) on NK cells, as well as to assess NK cell phenotype and function. The restorative effects of TIGIT blockade on NK cell cytotoxicity were evaluated through <jats:italic>in vitro<\/jats:italic> functional assays and <jats:italic>in vivo<\/jats:italic> animal models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Compared to healthy controls, DLBCL patients exhibited significantly reduced percentages and absolute numbers of NK cells. TIGIT expression was markedly upregulated on NK cells in DLBCL patients, while CD226 expression was downregulated; however, no significant difference in CD96 expression was observed. These alterations were associated with impaired NK cell function in DLBCL patients, including reduced secretion of activation factors such as granzyme B, perforin, and CD107a. Importantly, TIGIT blockade significantly enhanced the cytotoxic activity of NK cells against DLBCL cells in both <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> settings.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Dysregulated expression of TIGIT and its family molecules on NK cells contributes to NK cell dysfunction and promotes tumor immune escape in DLBCL. These findings highlight TIGIT as a promising therapeutic target for restoring NK cell-mediated antitumor immunity in DLBCL.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2025.1551061","type":"journal-article","created":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T06:37:48Z","timestamp":1743403068000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Increased TIGIT expression correlates with impaired NK cell function in diffuse large B-cell lymphoma"],"prefix":"10.3389","volume":"15","author":[{"given":"Hui","family":"Lu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liqiong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huafang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.pathol.2017.09.006","article-title":"Diffuse large B-cell lymphoma","volume":"50","author":"Li","year":"2018","journal-title":"Pathology"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.05.012","article-title":"Molecular pathogenesis of diffuse large B-cell lymphoma","volume":"23","author":"Lossos","year":"2005","journal-title":"J Clin oncology: Off J Am Soc Clin Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.31646","article-title":"Double hit and double expressors in lymphoma: Definition and treatment","volume":"124","author":"Riedell","year":"2018","journal-title":"Cancer"},{"key":"B4","doi-asserted-by":"publisher","first-page":"2040620721989579","DOI":"10.1177\/2040620721989579","article-title":"Rituximab in combination with cyclophosphamide,doxorubicin, vincristine, and prednisone (R-CHOP) in diffuse large B-cell lymphoma","volume":"12","author":"Candelaria","year":"2021","journal-title":"Ther Adv Hematol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/hon.v37.4","article-title":"Frontline treatment of diffuse large B-cell lymphoma: Beyond R-CHOP","volume":"7","author":"Mondello","year":"2019","journal-title":"Hematological Oncol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-03-769620","article-title":"Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study","volume":"130","author":"Crump","year":"2017","journal-title":"Blood"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1097\/CM9.0000000000001294","article-title":"R-CHOP resistance in diffuse large B-cell lymphoma: biological and molecular mechanisms","volume":"134","author":"Wang","year":"2020","journal-title":"Chin Med J"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-18-0439","article-title":"Immune profiling and quantitative analysis decipher the clinical role of immune-checkpoint expression in the tumor immune microenvironment of DLBCL","volume":"7","author":"Xu-Monette","year":"2019","journal-title":"Cancer Immunol Res"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.2147\/CMAR.S400013","article-title":"Drug-resistance mechanism and new targeted drugs and treatments of relapse and refractory DLBCL","volume":"15","author":"Zhang","year":"2023","journal-title":"Cancer Manage Res"},{"key":"B10","doi-asserted-by":"publisher","first-page":"5827","DOI":"10.3390\/cancers13225827","article-title":"Immunotherapy for diffuse large B-cell lymphoma: current landscape and future directions","volume":"13","author":"Modi","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.12998\/wjcc.v11.i30.7432","article-title":"Diffuse large B-cell lymphoma successfully treated with amplified natural killer therapy alone: A case report","volume":"11","author":"Nagai","year":"2023","journal-title":"World J Clin Cases"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3518","article-title":"Targeting natural killer cells in cancer immunotherapy","volume":"17","author":"Guillerey","year":"2016","journal-title":"Nat Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.11.045","article-title":"Gene regulatory programs conferring phenotypic identities to human NK cells","volume":"176","author":"Collins","year":"2019","journal-title":"Cell"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.v234.11","article-title":"NK cells: An attractive candidate for cancer therapy","volume":"234","author":"Valipour","year":"2019","journal-title":"J Cell Physiol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1111\/imm.2018.154.issue-3","article-title":"Natural killer cell cytotoxicity and its regulation by inhibitory receptors","volume":"154","author":"Kumar","year":"2018","journal-title":"Immunology"},{"key":"B16","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1186\/s12943-020-01238-x","article-title":"Natural killer cells in cancer biology and therapy","volume":"19","author":"Wu","year":"2020","journal-title":"Mol Cancer"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.1069378","article-title":"The immune checkpoint expression in the tumor immune microenvironment of DLBCL: Clinicopathologic features and prognosis","volume":"12","author":"Ma","year":"2022","journal-title":"Front Oncol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1186\/s13046-019-1259-z","article-title":"Combination of CTLA-4 and PD-1 blockers for treatment of cancer","volume":"38","author":"Rotte","year":"2019","journal-title":"J Exp Clin Cancer Res"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1007\/s11899-020-00589-y","article-title":"PD-1\/PD-L1 pathway and its blockade in patients with classic hodgkin lymphoma and non-hodgkin large-cell lymphomas","volume":"15","author":"Xie","year":"2020","journal-title":"Curr hematologic Malignancy Rep"},{"key":"B20","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1038\/ni.1674","article-title":"The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells","volume":"10","author":"Yu","year":"2009","journal-title":"Nat Immunol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1002\/eji.200839116","article-title":"A novel molecular interaction for the adhesion of follicular CD4 T cells to follicular DC","volume":"39","author":"Boles","year":"2009","journal-title":"Eur J Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0903474106","article-title":"The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity","volume":"106","author":"Stanietsky","year":"2009","journal-title":"Proc Natl Acad Sci United States America"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2019.11.013","article-title":"Tumor intrinsic and extrinsic immune functions of CD155","volume":"65","author":"O\u2019Donnell","year":"2020","journal-title":"Semin Cancer Biol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1038\/s41423-018-0168-y","article-title":"Targeting PVR (CD155) and its receptors in anti-tumor therapy","volume":"16","author":"Ku\u010dan Brli\u0107","year":"2019","journal-title":"Cell Mol Immunol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"216381","DOI":"10.1016\/j.canlet.2023.216381","article-title":"CD155 and its receptors in cancer immune escape and immunotherapy","volume":"573","author":"Zhou","year":"2023","journal-title":"Cancer Lett"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1111\/imr.2017.276.issue-1","article-title":"TIGIT and CD96: new checkpoint receptor targets for cancer immunotherapy","volume":"276","author":"Dougall","year":"2017","journal-title":"Immunol Rev"},{"key":"B27","doi-asserted-by":"publisher","first-page":"2","DOI":"10.5483\/BMBRep.2021.54.1.229","article-title":"Hitting the complexity of the TIGIT-CD96-CD112R-CD226 axis for next-generation cancer immunotherapy","volume":"54","author":"Jin","year":"2021","journal-title":"BMB Rep"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e006582","DOI":"10.1136\/jitc-2022-006582","article-title":"TIGIT is a key inhibitory checkpoint receptor in lymphoma","volume":"11","author":"Godfrey","year":"2023","journal-title":"J immunotherapy Cancer"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.01595","article-title":"Overexpression of TIGIT in NK and T cells contributes to tumor immune escape in myelodysplastic syndromes","volume":"10","author":"Meng","year":"2020","journal-title":"Front Oncol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-021-02978-5","article-title":"Increased TIGIT expressing NK cells with dysfunctional phenotype in AML patients correlated with poor prognosis","volume":"71","author":"Liu","year":"2022","journal-title":"Cancer immunology immunotherapy: CII"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00458","article-title":"Shaping of natural killer cell antitumor activity by ex vivo cultivation","volume":"8","author":"Granzin","year":"2017","journal-title":"Front Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1084\/jem.173.4.869","article-title":"Induction of interferon gamma production by natural killer cell stimulatory factor: characterization of the responder cells and synergy with other inducers","volume":"173","author":"Chan","year":"1991","journal-title":"J Exp Med"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1757","DOI":"10.3390\/cells9081757","article-title":"Engineering the bridge between innate and adaptive immunity for cancer immunotherapy: Focus on \u03b3\u03b4 T and NK Cells","volume":"9","author":"Morandi","year":"2020","journal-title":"Cells"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00293","article-title":"Role of distinct natural killer cell subsets in anticancer response","volume":"8","author":"Stabile","year":"2017","journal-title":"Front Immunol"},{"key":"B35","article-title":"Lower number and percentage of activated natural killer cells in colorectal cancer patients","volume":"54","author":"Vidyani","year":"2022","journal-title":"Acta Med Indonesiana"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2008.08.012","article-title":"Functional impairment in circulating and intrahepatic NK cells and relative mechanism in hepatocellular carcinoma patients","volume":"129","author":"Cai","year":"2008","journal-title":"Clin Immunol (Orlando Fla.)"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2017.1409322","article-title":"NK cell activation and recovery of NK cell subsets in lymphoma patients after obinutuzumab and lenalidomide treatment","volume":"7","author":"Vo","year":"2017","journal-title":"Oncoimmunology"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1168684","article-title":"Skin infiltrating NK cells in cutaneous T-cell lymphoma are increased in number and display phenotypic alterations partially driven by the tumor","volume":"14","author":"Scheffschick","year":"2023","journal-title":"Front Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02278","article-title":"NK cell metabolism and tumor microenvironment","volume":"10","author":"Terr\u00e9n","year":"2019","journal-title":"Front Immunol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-018-0061-z","article-title":"Natural killer cells and other innate lymphoid cells in cancer","volume":"18","author":"Chiossone","year":"2018","journal-title":"Nat Rev Immunol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1810804","DOI":"10.1155\/2022\/1810804","article-title":"Combination blockade of the IL6R\/STAT-3 axis with TIGIT and its impact on the functional activity of NK cells against prostate cancer cells","author":"Gonz\u00e1lez-Ochoa","year":"2022","journal-title":"J Immunol Res"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-02-481788","article-title":"Genome-wide DNA methylation analysis identifies hypomethylated genes regulated by FOXP3 in human regulatory T cells","volume":"122","author":"Zhang","year":"2013","journal-title":"Blood"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.7.3994","article-title":"Cutting edge: CD96 (tactile) promotes NK cell-target cell adhesion by interacting with the poliovirus receptor (CD155)","volume":"172","author":"Fuchs","year":"2004","journal-title":"J Immunol (Baltimore Md.: 1950)"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2022-004711","article-title":"TIGIT-CD226-PVR axis: advancing immune checkpoint blockade for cancer immunotherapy","volume":"10","author":"Chiang","year":"2022","journal-title":"J immunotherapy Cancer"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2016.10.002","article-title":"TIGIT: a key inhibitor of the cancer immunity cycle","volume":"38","author":"Manieri","year":"2017","journal-title":"Trends Immunol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2012.141","article-title":"Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells","volume":"20","author":"Liu","year":"2013","journal-title":"Cell Death differentiation"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.572420","article-title":"T-cell immunoglobulin and ITIM domain (TIGIT) receptor\/poliovirus receptor (PVR) ligand engagement suppresses interferon-\u03b3 production of natural killer cells via \u03b2-arrestin 2-mediated negative signaling","volume":"289","author":"Li","year":"2014","journal-title":"J Biol Chem"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V97.10.3146","article-title":"Human natural killer cells: a unique innate immunoregulatory role for the CD56(bright) subset","volume":"97","author":"Cooper","year":"2001","journal-title":"Blood"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-18-0725","article-title":"Blockade of TIGIT\/CD155 signaling reverses T-cell exhaustion and enhances antitumor capability in head and neck squamous cell carcinoma","volume":"7","author":"Wu","year":"2019","journal-title":"Cancer Immunol Res"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-20-0464","article-title":"Restoration of T-cell effector function, depletion of tregs, and direct killing of tumor cells: the multiple mechanisms of action of a-TIGIT antagonist antibodies","volume":"20","author":"Preillon","year":"2021","journal-title":"Mol Cancer Ther"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1002\/cti2.v10.10","article-title":"TIGIT blockade enhances NK cell activity against autologous HIV-1-infected CD4+ T cells","volume":"10","author":"Holder","year":"2021","journal-title":"Clin Trans Immunol"},{"key":"B52","doi-asserted-by":"publisher","first-page":"216300","DOI":"10.1016\/j.canlet.2023.216300","article-title":"TIGIT immune checkpoint blockade enhances immunity of human peripheral blood NK cells against castration-resistant prostate cancer","volume":"568","author":"Wang","year":"2023","journal-title":"Cancer Lett"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2025.1551061\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T06:37:50Z","timestamp":1743403070000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2025.1551061\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,31]]},"references-count":52,"alternative-id":["10.3389\/fonc.2025.1551061"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2025.1551061","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,31]]},"article-number":"1551061"}}