{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T09:47:23Z","timestamp":1791798443990,"version":"4.3.4"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T00:00:00Z","timestamp":1790380800000},"content-version":"vor","delay-in-days":268,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"John Goldman Fellowship"},{"DOI":"10.13039\/100015763","name":"Leukaemia UK","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015763","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100015570","name":"Blood Cancer UK","doi-asserted-by":"publisher","award":["23023"],"award-info":[{"award-number":["23023"]}],"id":[{"id":"10.13039\/501100015570","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Selinexor is a first-in-class selective inhibitor of nuclear export targeting exportin-1 (XPO1) and approved for the treatment of multiple myeloma (MM). Selinexor has previously been shown to enhance natural killer (NK) cell activation against lymphoma cells via disruption of the NKG2A:HLA-E immune checkpoint axis. MM cell lines (L363, U266, MM.1S) and primary myeloma cells isolated from the bone marrow of patients were exposed to selinexor (50\u20132000\u2005nM) with or without IFN\u03b3 or IL-6 to mimic the tumour microenvironment (TME). Surface HLA-E and total HLA class I were quantified by flow cytometry. Immunoblotting and a range of functional assays were used to examine the effect of selinexor on NK cell effector function against MM. Selinexor downregulated surface HLA-E expression on MM cell lines and primary myeloma cells. This improved the activation of NKG2A+ NK cells, NK cell-specific lysis of MM cell lines and antibody-dependent cellular cytotoxicity (ADCC) with the therapeutic antibodies daratumumab and elotuzumab. This improvement was also observed in the presence of TME-mimicking signals IFN\u03b3 and IL-6. Pre-treatment of MM cells with selinexor for 24\u2005hours prior to daratumumab resulted in optimal ADCC. These data reveal that selinexor selectively disrupts the NKG2A:HLA-E immune checkpoint axis in MM and enhances NK cell activation and ADCC against MM cells. These findings provide a mechanistic rationale for investigating combinations of selinexor with approved therapeutic antibodies in MM and suggest that treatment timing may be an important consideration in the design of combination regimens.<\/jats:p>","DOI":"10.1093\/cei\/uxag059","type":"journal-article","created":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T06:44:30Z","timestamp":1790405070000},"source":"Crossref","is-referenced-by-count":0,"title":["Selinexor potentiates NK cell activation against multiple myeloma"],"prefix":"10.1093","volume":"220","author":[{"given":"Daniel T","family":"Harding","sequence":"first","affiliation":[{"name":"School of Clinical and Experimental Sciences, University of Southampton , Southampton ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lara V","family":"Graham","sequence":"additional","affiliation":[{"name":"School of Clinical and Experimental Sciences, University of Southampton , Southampton ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura G","family":"Bartlett","sequence":"additional","affiliation":[{"name":"School of Clinical and Experimental Sciences, University of Southampton , Southampton ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy","family":"Gudgeon","sequence":"additional","affiliation":[{"name":"Department of Immunology and Immunotherapy, University of Birmingham , Birmingham ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack G","family":"Fisher","sequence":"additional","affiliation":[{"name":"School of Clinical and Experimental Sciences, University of Southampton , Southampton ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J","family":"Walker","sequence":"additional","affiliation":[{"name":"Karyopharm Therapeutics , Newton, MA \u00a0","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trinayan","family":"Kashyap","sequence":"additional","affiliation":[{"name":"Karyopharm Therapeutics , Newton, MA \u00a0","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte E","family":"Brookes","sequence":"additional","affiliation":[{"name":"School of Clinical and Experimental Sciences, University of Southampton , Southampton ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aidan","family":"Haslam","sequence":"additional","affiliation":[{"name":"Department of Immunology and Immunotherapy, University of Birmingham , Birmingham ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham","family":"McIlroy","sequence":"additional","affiliation":[{"name":"Department of Immunology and Immunotherapy, University of Birmingham , Birmingham ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy","family":"Pratt","sequence":"additional","affiliation":[{"name":"Department of Immunology and Immunotherapy, University of Birmingham , Birmingham ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben M","family":"Amram","sequence":"additional","affiliation":[{"name":"School of Clinical and Experimental Sciences, University of Southampton , Southampton ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgia","family":"Francis","sequence":"additional","affiliation":[{"name":"School of Clinical and Experimental Sciences, University of Southampton , Southampton ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2077-089X","authenticated-orcid":false,"given":"Mark S","family":"Cragg","sequence":"additional","affiliation":[{"name":"Antibody and Vaccine Group, Centre for Cancer Immunology, Faculty of Medicine, University of Southampton , Southampton ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salim I","family":"Khakoo","sequence":"additional","affiliation":[{"name":"School of Clinical and Experimental Sciences, University of Southampton , Southampton ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Dimeloe","sequence":"additional","affiliation":[{"name":"Department of Immunology and Immunotherapy, University of Birmingham , Birmingham ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1099-3985","authenticated-orcid":false,"given":"Matthew D","family":"Blunt","sequence":"additional","affiliation":[{"name":"School of Clinical and Experimental Sciences, University of Southampton , Southampton ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,9,26]]},"reference":[{"key":"2026101205071434800_uxag059-B1","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1172\/JCI129205","article-title":"Immunotherapy of multiple myeloma","volume":"130","author":"Minnie","year":"2020","journal-title":"J Clin Invest"},{"key":"2026101205071434800_uxag059-B2","doi-asserted-by":"crossref","first-page":"2343","DOI":"10.1038\/s41375-019-0561-2","article-title":"Relapsed refractory multiple myeloma: a comprehensive overview","volume":"33","author":"Bazarbachi","year":"2019","journal-title":"Leukemia"},{"key":"2026101205071434800_uxag059-B3","doi-asserted-by":"crossref","first-page":"2334","DOI":"10.1182\/blood.2019004332","article-title":"The JAK-STAT pathway regulates CD38 on myeloma cells in the bone marrow microenvironment: therapeutic implications","volume":"136","author":"Ogiya","year":"2020","journal-title":"Blood"},{"key":"2026101205071434800_uxag059-B4","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1182\/blood-2024-194041","article-title":"An IFN\u03b3-mediated immune inflamed microenvironment state in multiple myeloma with TP53 loss that can be therapeutically exploited","volume":"144","author":"Larrayoz","year":"2024","journal-title":"Blood"},{"key":"2026101205071434800_uxag059-B5","doi-asserted-by":"crossref","first-page":"1575079","DOI":"10.3389\/fimmu.2025.1575079","article-title":"Multi-omics reveals immune features in immune and non-immune cells, an IFN-gamma\/IFN-alpha-B2M positive feedback loop, and targeted metabolic therapy in multiple myeloma","volume":"16","author":"Li","year":"2025","journal-title":"Front Immunol"},{"key":"2026101205071434800_uxag059-B6","doi-asserted-by":"crossref","first-page":"e17298","DOI":"10.1016\/j.heliyon.2023.e17298","article-title":"Characterization of monoclonal gammopathy of undetermined significance progression to multiple myeloma through meta-analysis of GEO data","volume":"9","author":"Aljabban","year":"2023","journal-title":"Heliyon"},{"key":"2026101205071434800_uxag059-B7","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1007\/s40265-019-01188-9","article-title":"Selinexor: first global approval","volume":"79","author":"Syed","year":"2019","journal-title":"Drugs"},{"key":"2026101205071434800_uxag059-B8","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/s13045-020-00903-4","article-title":"XPO1-dependent nuclear export as a target for cancer therapy","volume":"13","author":"Azizian","year":"2020","journal-title":"J Hematol Oncol"},{"key":"2026101205071434800_uxag059-B9","doi-asserted-by":"crossref","first-page":"6196","DOI":"10.1093\/emboj\/19.22.6196","article-title":"Nuclear export signal located within the DNA-binding domain of the STAT1transcription factor","volume":"19","author":"McBride","year":"2000","journal-title":"EMBO J"},{"key":"2026101205071434800_uxag059-B10","doi-asserted-by":"crossref","first-page":"2493","DOI":"10.3324\/haematol.2024.287053","article-title":"A phase IIb study of selinexor in combination with daratumumab in patients with daratumumab-refractory multiple myeloma","volume":"110","author":"Biran","year":"2025","journal-title":"Haematologica"},{"key":"2026101205071434800_uxag059-B11","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1158\/1535-7163.MCT-17-0998","article-title":"Antibody-dependent cellular phagocytosis by macrophages is a novel mechanism of action of elotuzumab","volume":"17","author":"Kurdi","year":"2018","journal-title":"Mol Cancer Ther"},{"key":"2026101205071434800_uxag059-B12","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1182\/bloodadvances.2017006866","article-title":"Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma","volume":"1","author":"Casneuf","year":"2017","journal-title":"Blood Adv"},{"key":"2026101205071434800_uxag059-B13","doi-asserted-by":"crossref","first-page":"1840","DOI":"10.4049\/jimmunol.1003032","article-title":"Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors","volume":"186","author":"de Weers","year":"2011","journal-title":"J Immunol"},{"key":"2026101205071434800_uxag059-B14","doi-asserted-by":"crossref","first-page":"1429879","DOI":"10.1155\/2024\/1429879","article-title":"Elotuzumab enhances CD16-independent NK cell-mediated cytotoxicity against myeloma cells by upregulating several NK cell-enhancing genes","volume":"2024","author":"Wang","year":"2024","journal-title":"J Immunol Res"},{"key":"2026101205071434800_uxag059-B15","doi-asserted-by":"crossref","first-page":"3007","DOI":"10.1182\/blood.2024026455","article-title":"The bone marrow NK-cell profile predicts MRD negativity in patients with multiple myeloma treated with daratumumab-based therapy","volume":"145","author":"Korst","year":"2025","journal-title":"Blood"},{"key":"2026101205071434800_uxag059-B16","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1007\/s00262-015-1694-4","article-title":"Optimal selection of natural killer cells to kill myeloma: the role of HLA-E and NKG2A","volume":"64","author":"Sarkar","year":"2015","journal-title":"Cancer Immunol Immunother"},{"key":"2026101205071434800_uxag059-B17","doi-asserted-by":"crossref","first-page":"1777","DOI":"10.1038\/s41375-024-02303-w","article-title":"CREB1 promotes expression of immune checkpoint HLA-E leading to immune escape in multiple myeloma","volume":"38","author":"Ismael","year":"2024","journal-title":"Leukemia"},{"key":"2026101205071434800_uxag059-B18","doi-asserted-by":"crossref","first-page":"2411","DOI":"10.1182\/blood-2021-144836","article-title":"Selinexor enhances NK cell activation against lymphoma cells via downregulation of HLA-E","volume":"138","author":"Fisher","year":"2021","journal-title":"Blood"},{"key":"2026101205071434800_uxag059-B19","doi-asserted-by":"crossref","first-page":"2036","DOI":"10.1038\/s41375-023-01984-z","article-title":"XPO1 inhibition sensitises CLL cells to NK cell mediated cytotoxicity and overcomes HLA-E expression","volume":"37","author":"Fisher","year":"2023","journal-title":"Leukemia"},{"key":"2026101205071434800_uxag059-B20","doi-asserted-by":"crossref","first-page":"ltaf029","DOI":"10.1093\/immadv\/ltaf029","article-title":"CD40L and IL-4 suppress NK cell-mediated ADCC through the HLA-E:NKG2A axis","volume":"5","author":"Graham","year":"2025","journal-title":"Immunother Adv"},{"key":"2026101205071434800_uxag059-B21","doi-asserted-by":"crossref","first-page":"2387","DOI":"10.1038\/s41467-019-10335-5","article-title":"Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition","volume":"10","author":"Pereira","year":"2019","journal-title":"Nat Commun"},{"key":"2026101205071434800_uxag059-B22","doi-asserted-by":"crossref","first-page":"2002","DOI":"10.1038\/s41589-025-02058-0","article-title":"SINE compounds activate exportin 1 degradation through an allosteric mechanism","volume":"21","author":"Wing","year":"2025","journal-title":"Nat Chem Biol"},{"key":"2026101205071434800_uxag059-B23","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1038\/s41408-024-01050-6","article-title":"Induction of NK cell reactivity against acute myeloid leukemia by Fc-optimized CD276 (B7-H3) antibody","volume":"14","author":"Stefa\u0144czyk","year":"2024","journal-title":"Blood Cancer J"},{"key":"2026101205071434800_uxag059-B24","doi-asserted-by":"crossref","first-page":"2743","DOI":"10.3389\/fimmu.2018.02743","article-title":"Enhancing the activation and releasing the brakes: a double hit strategy to improve NK cell cytotoxicity against multiple myeloma","volume":"9","author":"Tognarelli","year":"2018","journal-title":"Front Immunol"},{"key":"2026101205071434800_uxag059-B25","doi-asserted-by":"crossref","first-page":"2081415","DOI":"10.1080\/2162402X.2022.2081415","article-title":"CRISPR-Cas9 based gene editing of the immune checkpoint NKG2A enhances NK cell mediated cytotoxicity against multiple myeloma","volume":"11","author":"Bexte","year":"2022","journal-title":"OncoImmunology"},{"key":"2026101205071434800_uxag059-B26","doi-asserted-by":"crossref","first-page":"1002310","DOI":"10.37349\/etat.2025.1002310","article-title":"Modulation of anti-tumour immunity by XPO1 inhibitors","volume":"6","author":"Fisher","year":"2025","journal-title":"Explor Target Antitumor Ther"},{"key":"2026101205071434800_uxag059-B27","doi-asserted-by":"crossref","first-page":"e70403","DOI":"10.1002\/ctm2.70403","article-title":"Decoding MHC loss: molecular mechanisms and implications for immune resistance in cancer","volume":"15","author":"Lin","year":"2025","journal-title":"Clin Transl Med"},{"key":"2026101205071434800_uxag059-B28","doi-asserted-by":"crossref","first-page":"6741","DOI":"10.3390\/ijms22136741","article-title":"MHC class I deficiency in solid tumors and therapeutic strategies to overcome it","volume":"22","author":"Shklovskaya","year":"2021","journal-title":"Int J Mol Sci"},{"key":"2026101205071434800_uxag059-B29","doi-asserted-by":"crossref","first-page":"4010","DOI":"10.1182\/blood-2025-4010","article-title":"Selinexor, mezigdomide, and dexamethasone in patients with relapsed\/refractory multiple myeloma who relapsed or are ineligible for T-cell\u2013redirecting therapy: stomp phase 1 results","volume":"146","author":"Mo","year":"2025","journal-title":"Blood"},{"key":"2026101205071434800_uxag059-B30","doi-asserted-by":"crossref","first-page":"100009","DOI":"10.1016\/j.bict.2025.100009","article-title":"Selinexor-based treatments are associated with increased expression of T-cell activation markers in multiple myeloma","volume":"1","author":"Kang","year":"2025","journal-title":"Blood Immunol Cell Ther"},{"key":"2026101205071434800_uxag059-B31","doi-asserted-by":"crossref","first-page":"217","DOI":"10.3390\/cancers13020217","article-title":"The role of tumor microenvironment in multiple myeloma development and progression","volume":"13","author":"Garc\u00eda-Ortiz","year":"2021","journal-title":"Cancers (Basel)"},{"key":"2026101205071434800_uxag059-B32","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/s41408-021-00440-4","article-title":"Relapsed multiple myeloma demonstrates distinct patterns of immune microenvironment and malignant cell-mediated immunosuppression","volume":"11","author":"Visram","year":"2021","journal-title":"Blood Cancer J"},{"key":"2026101205071434800_uxag059-B33","doi-asserted-by":"crossref","first-page":"105115","DOI":"10.1016\/j.antiviral.2021.105115","article-title":"Selinexor, a novel selective inhibitor of nuclear export, reduces SARS-CoV-2 infection and protects the respiratory system in vivo","volume":"192","author":"Kashyap","year":"2021","journal-title":"Antiviral Res"},{"key":"2026101205071434800_uxag059-B34","doi-asserted-by":"crossref","first-page":"1792","DOI":"10.1182\/blood-2023-186674","article-title":"Use of combination therapies including the XPO1 inhibitor selinexor in is a potential effective therapeutic strategy to treat myelofibrosis patients","volume":"142","author":"Lu","year":"2023","journal-title":"Blood"},{"key":"2026101205071434800_uxag059-B35","doi-asserted-by":"crossref","first-page":"S437","DOI":"10.1016\/S2152-2650(24)01443-5","article-title":"Selinexor and ruxolitinib impact on symptom burden in patients with myelofibrosis is potentially driven by inhibition of NF-\u03baB and activation of P53 pathways","volume":"24","author":"Tantravahi","year":"2024","journal-title":"Cl Lymph Myelom Leuk"},{"key":"2026101205071434800_uxag059-B36","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1182\/blood-2023-180844","article-title":"Selinexor plus ruxolitinib in JAK inhibitor (JAKi)-naive patients with myelofibrosis: long term follow up from XPORT-MF-034 suggestive of disease modification","volume":"142","author":"Tantravahi","year":"2023","journal-title":"Blood"},{"key":"2026101205071434800_uxag059-B37","doi-asserted-by":"crossref","first-page":"2231","DOI":"10.3390\/cells9102231","article-title":"Selinexor sensitizes TRAIL-R2-positive TNBC cells to the activity of TRAIL-R2xCD3 bispecific antibody","volume":"9","author":"Martini","year":"2020","journal-title":"Cells"},{"key":"2026101205071434800_uxag059-B38","doi-asserted-by":"crossref","first-page":"7413","DOI":"10.1182\/blood-2022-164443","article-title":"Sequential administration of selinexor then CD19 CAR-T cells exhibits enhanced efficacy in a mouse model of human non-Hodgkin's lymphoma","volume":"140","author":"Stadel","year":"2022","journal-title":"Blood"},{"key":"2026101205071434800_uxag059-B39","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1158\/0008-5472.CAN-24-0886","article-title":"The functional transcriptomic landscape informs therapeutic strategies in multiple myeloma","volume":"85","author":"Sudalagunta","year":"2025","journal-title":"Cancer Res"},{"key":"2026101205071434800_uxag059-B40","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1056\/NEJMoa2024850","article-title":"Idecabtagene vicleucel in relapsed and refractory multiple myeloma","volume":"384","author":"Munshi","year":"2021","journal-title":"N Engl J Med"},{"key":"2026101205071434800_uxag059-B41","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1016\/j.cell.2018.10.014","article-title":"Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells","volume":"175","author":"Andr\u00e9","year":"2018","journal-title":"Cell"},{"key":"2026101205071434800_uxag059-B42","doi-asserted-by":"crossref","first-page":"6081","DOI":"10.1016\/j.cell.2021.11.016","article-title":"An NK-like CAR T cell transition in CAR T cell dysfunction","volume":"184","author":"Good","year":"2021","journal-title":"Cell"}],"container-title":["Clinical and Experimental Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/cei\/advance-article-pdf\/doi\/10.1093\/cei\/uxag059\/71400633\/uxag059.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/220\/1\/uxag059\/71400633\/uxag059.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/220\/1\/uxag059\/71400633\/uxag059.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T09:07:23Z","timestamp":1791796043000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cei\/article\/doi\/10.1093\/cei\/uxag059\/8836443"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026]]},"references-count":42,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1,6]]}},"URL":"https:\/\/doi.org\/10.1093\/cei\/uxag059","relation":{},"ISSN":["0009-9104","1365-2249"],"issn-type":[{"value":"0009-9104","type":"print"},{"value":"1365-2249","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026]]},"published":{"date-parts":[[2026]]},"article-number":"uxag059"}}