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We found that MM patient blood NK cell frequencies were normal with increased activating receptors and cytotoxic granules, without evidence of functional exhaustion. Despite this activated state, MM target cells were resistant to conventional NK cells by unclear mechanisms. Memory-like (ML) NK cells are generated after brief activation via the interleukin (IL)-12, IL-15, and IL-18 receptors and exhibit multiple enhanced antitumor properties. ML NK cell differentiation improved healthy donor and MM patient NK cell responses against MM target cells, in vitro and in vivo in immunodeficient murine xenograft models. Moreover, incorporating NKG2A checkpoint blockade to overcome HLA-E\u2013induced inhibition further enhanced ML NK cell responses against MM in vitro and in vivo. Because activating receptor recognition of MM by ML NK cells was inadequate, strategies to improve this were investigated. Utilizing anti-SLAMF7 monoclonal antibody (elotuzumab) or anti-BCMA chimeric antigen receptors resulted in robust increases in ML NK cell functional responses against MM. In summary, ML differentiation enhances NK cell attack against myeloma, and combination with approaches to block inhibitory checkpoints and promote MM-specific activation are promising translational NK cell strategies for MM immunotherapy.<\/jats:p>","DOI":"10.1093\/jimmun\/vkae004","type":"journal-article","created":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T14:57:11Z","timestamp":1737644231000},"page":"1-11","source":"Crossref","is-referenced-by-count":5,"title":["Memory-like NK cell differentiation, inhibitory NKG2A blockade, and improved recognition via antibody or CAR engineering combine to enhance NK cell attack against multiple myeloma"],"prefix":"10.1093","volume":"214","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3916-8666","authenticated-orcid":false,"given":"Alice Y","family":"Zhou","sequence":"first","affiliation":[{"name":"Division of Oncology, Department of Medicine, Washington University School of Medicine in St. Louis , St. Louis, MO,","place":["United 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MO,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynne","family":"Marsala","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Medicine, Washington University School of Medicine in St. Louis , St. Louis, MO,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2683-7189","authenticated-orcid":false,"given":"Mark","family":"Foster","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Medicine, Washington University School of Medicine in St. Louis , St. Louis, MO,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9158-3464","authenticated-orcid":false,"given":"Jennifer A","family":"Foltz","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Medicine, Washington University School of Medicine in St. Louis , St. Louis, MO,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carly C","family":"Neal","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Medicine, Washington University School of Medicine in St. Louis , St. Louis, MO,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1009-2247","authenticated-orcid":false,"given":"David A","family":"Russler-Germain","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Medicine, Washington University School of Medicine in St. Louis , St. Louis, MO,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7361-5407","authenticated-orcid":false,"given":"Lyra","family":"Morina","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Medicine, Washington University School of Medicine in St. 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