{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T19:57:17Z","timestamp":1791835037914,"version":"4.3.4"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T00:00:00Z","timestamp":1756339200000},"content-version":"vor","delay-in-days":241,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"John Goldman Fellowship Follow-up"},{"DOI":"10.13039\/100011726","name":"Wessex Medical Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011726","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["M019829"],"award-info":[{"award-number":["M019829"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["S009338"],"award-info":[{"award-number":["S009338"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C9380\/A18084"],"award-info":[{"award-number":["C9380\/A18084"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University of Southampton Cancer Immunology Talent Fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,12,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Anti-CD20 antibodies are first-line treatments for B cell malignancies. Natural killer (NK) cells are important mediators of anti-CD20 antibody efficacy in humans through antibody-dependent cellular cytotoxicity (ADCC). In B cell malignancies, the lymph nodes are a critical site of pathology and the T cell-derived signals CD40L and IL-4 within the lymph node microenvironment can mediate tumour proliferation, survival and resistance to pro-apoptotic therapy. CD40L and IL-4 have recently been shown to inhibit NK cell activation against chronic lymphocytic leukaemia (CLL) cells via the HLA-E:NKG2A immune checkpoint axis. However, the effect of these signals on NK cell-mediated ADCC of malignant B cells is unclear.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Using a combination of clinical samples, murine models, flow cytometry, immunoblotting, immunohistochemistry, ELISA, bioinformatics and functional assays, we examined the impact of lymph node-mimicking conditions on NK cell-mediated ADCC against malignant B cells. Exogenous CD40L and IL-4 were used to mimic T-B cell interactions in 2D malignant B cell cultures, in addition to a 3D spheroid model of T cell-dependent CLL proliferation.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>CD40L and IL-4 increased HLA-E expression on the surface of primary CLL cells and non-Hodgkin\u2019s lymphoma (NHL) cell lines, and this decreased NK cell-mediated ADCC via ligation of the inhibitory receptor NKG2A. High HLA-E surface expression was observed in lymph node FFPE sections of CLL and NHL patients and in a 3D ex vivo lymph node-mimicking model of CLL. NKG2A blockade potentiated NK cell-mediated ADCC against malignant B cells treated with CD40L and IL-4 and improved anti-CD20 antibody therapy in a murine model of B cell lymphoma.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>These results reveal a novel mechanism of resistance to anti-CD20 therapy in B cell malignancies and demonstrate that the combination of anti-NKG2A with anti-CD20 could improve the treatment of patients with CLL or NHL.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/immadv\/ltaf029","type":"journal-article","created":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T09:53:36Z","timestamp":1756374816000},"source":"Crossref","is-referenced-by-count":4,"title":["CD40L and IL-4 suppress NK cell-mediated antibody-dependent cellular cytotoxicity through the HLA-E:NKG2A axis"],"prefix":"10.1093","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-5420-9020","authenticated-orcid":false,"given":"Lara V","family":"Graham","sequence":"first","affiliation":[{"name":"School of Clinical and Experimental Sciences, University of Southampton , Southampton ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludmila","family":"Horehajova","sequence":"additional","affiliation":[{"name":"School of Clinical and Experimental Sciences, University of Southampton , Southampton ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco V","family":"Haselager","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam , Meibergdreef ,","place":["The Netherlands"]},{"name":"Lymphoma and Myeloma Centre Amsterdam, LYMMCARE , Amsterdam ,","place":["The Netherlands"]},{"name":"Cancer Centre Amsterdam, Amsterdam 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Cancer Immunology , Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell B","family":"Foxall","sequence":"additional","affiliation":[{"name":"School of Cancer Sciences, University of Southampton , Southampton ,","place":["United Kingdom"]},{"name":"Antibody and Vaccine Group, Centre for Cancer Immunology, Faculty of Medicine, University of Southampton , Southampton ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mel","family":"John","sequence":"additional","affiliation":[{"name":"School of Clinical and Experimental Sciences, University of Southampton , Southampton ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerry L","family":"Cox","sequence":"additional","affiliation":[{"name":"School of Cancer Sciences, University of Southampton , Southampton ,","place":["United Kingdom"]},{"name":"Antibody and Vaccine Group, Centre for Cancer 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