{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T06:28:26Z","timestamp":1787725706887,"version":"build-2784847793"},"reference-count":20,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,3,25]],"date-time":"2024-03-25T00:00:00Z","timestamp":1711324800000},"content-version":"vor","delay-in-days":84,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010890","name":"Chinese Government Scholarship","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010890","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin &amp; Trans Imm"],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objectives<\/jats:title><jats:p>The rapid recognition of epigenetic manipulation's potential in restricting cancer cell capabilities spurred translational initiatives, including histone deacetylase inhibitors (HDACis). Clinical trials on multiple myeloma (MM) demonstrated substantial benefits of HDACis, coupled with promising outcomes from cytokine\u2010induced killer cell (CIK) immunotherapy. Intriguingly, the unexplored synergy of HDACis and CIK cell immunotherapy in MM prompted our study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We examined clinically relevant HDACis (panobinostat\/LBH589 and romidepsin) alongside CIK cells derived from peripheral blood mononuclear cells across diverse MM cell lines (U266, RPMI8226, OPM\u20102 and NCI\u2010H929). Utilising various <jats:italic>in vitro<\/jats:italic> methodologies, we investigated how HDACis enhance CIK cell lysis of myeloma cells through NKG2D\/NKG2D ligand interactions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The results of our analysis indicated several key findings. (1) Enhanced cytotoxicity of CIK cells in MM cells when combined with HDACis. (2) Significant increase in apoptosis, suggesting HDACis and CIK may together enhance apoptotic effects in specific MM cell lines. (3) Elevated IFN\u2010\u03b3 secretion and alterations in granzyme B\u00a0secretion because of the independent activity of HDACis. (4) Notably, HDACis increased the expression of MICA\/B and ULBP2, crucial for inducing antitumor cytotoxicity of NKT\u00a0cells. Validation through NKG2D receptor blocking in CIK cells with a purified mouse antihuman NKG2D antibody further supported our findings.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our analyses provide sufficient evidence to consider this clinically forgotten instance (HDACis\u2010CIK cell combination) as a therapeutic priority for MM treatment. Furthermore, we suggest that NKG2D\/NKG2D\u2010ligand interactions activating NK\/NKT\u00a0cells may contribute to enhanced myeloma cell lysis in response to HDACis treatment by CIK cells.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cti2.1500","type":"journal-article","created":{"date-parts":[[2024,3,25]],"date-time":"2024-03-25T11:34:11Z","timestamp":1711366451000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Synergistic integration of histone deacetylase inhibitors apparently enhances the cytokine\u2010induced killer cell efficiency in multiple myeloma via the NKG2D pathway"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9854-5329","authenticated-orcid":false,"given":"Jingjing","family":"Pu","sequence":"first","affiliation":[{"name":"Department of Integrated Oncology, Center for Integrated Oncology (CIO) Bonn University Hospital Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Integrated Oncology, Center for Integrated Oncology (CIO) Bonn University Hospital Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Liu","sequence":"additional","affiliation":[{"name":"Translational Biogerontology Lab German Center for Neurodegenerative Diseases (DZNE)  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Hou","sequence":"additional","affiliation":[{"name":"Renji Hospital, School of Medicine Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingo GH","family":"Schmidt\u2010Wolf","sequence":"additional","affiliation":[{"name":"Department of Integrated Oncology, Center for Integrated Oncology (CIO) Bonn University Hospital Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,3,25]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.4161\/15592294.2014.983367"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1080\/07357907.2021.1872593"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/med.21972"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers11040475"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2020.112831"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1157366"},{"key":"e_1_2_9_8_1","first-page":"295","article-title":"Balancing\u00a0the interplay of histone deacetylases and non\u2010coding genomes: A step closer to understand the landscape of cancer treatment","volume":"16","author":"Pu J","year":"2023","journal-title":"BMC Med Genet"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-013-1231-0"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-14-370"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-021-02184-2"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.2169\/internalmedicine.49.3996"},{"key":"e_1_2_9_13_1","first-page":"13146","article-title":"Immunomodulatory effect of DC\/CIK combined with chemotherapy in multiple myeloma and the clinical efficacy","volume":"8","author":"Zhao X","year":"2015","journal-title":"Int J Clin Exp Pathol"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.2147\/DDDT.S146959"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18050945"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-02-336321"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-008-0635-x"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(14)70440-1"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41401-021-00728-y"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.174.1.139"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-8885-3_8"}],"container-title":["Clinical &amp; 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