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Herein, we identify non-classical major histocompatibility complex (MHC) class I molecule HLA-E as a major contributing factor in immune escape. Clinically, HLA-E expression correlates with aggressive disease features such as t(4;14) and CD56 expression and is induced by IFN-gamma (IFN-\u03b3) in the TME. We discovered that HLA-E is regulated by cAMP responsive element binding protein 1 (CREB1) transcription factor by direct promoter binding; genomic and pharmacological inhibition of CREB1 reduced HLA-E levels even in the presence of IFN-\u03b3 or IFN-\u03b3 activating agents, such as immunomodulatory drugs and panobinostat. HLA-E binds to natural killer group 2A (NKG2A), delivering an inhibitor signal to natural killer (NK) cells. Treatment with a\u00a0CREB1 inhibitor was able to restore NK cell-mediated cytotoxicity against MM cell lines and patient samples. In conclusion, our results strongly demonstrate that CREB1 inhibition promotes anti-tumoral immunity in MM by limiting HLA-E expression and enhancing the activity of NK cells.<\/jats:p>","DOI":"10.1038\/s41375-024-02303-w","type":"journal-article","created":{"date-parts":[[2024,6,20]],"date-time":"2024-06-20T14:03:01Z","timestamp":1718892181000},"page":"1777-1786","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["CREB1 promotes expression of immune checkpoint HLA-E leading to immune escape in multiple myeloma"],"prefix":"10.1038","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5635-1061","authenticated-orcid":false,"given":"Aya","family":"Ismael","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allen J.","family":"Robinette","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laila","family":"Huric","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie","family":"Schuetz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kameron","family":"Dona","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Don","family":"Benson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuele","family":"Cocucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8676-7840","authenticated-orcid":false,"given":"Francesca","family":"Cottini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,20]]},"reference":[{"key":"2303_CR1","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1016\/S0140-6736(21)00135-5","volume":"397","author":"N van de Donk","year":"2021","unstructured":"van de Donk N, Pawlyn C, Yong KL. 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