{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T22:00:50Z","timestamp":1790805650789,"version":"4.1.0"},"reference-count":93,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,1,29]],"date-time":"2021-01-29T00:00:00Z","timestamp":1611878400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Cellular immunotherapy using chimeric antigen receptors (CARs) so far has almost exclusively used autologous peripheral blood-derived T cells as immune effector cells. However, harvesting sufficient numbers of T cells is often challenging in heavily pre-treated patients with malignancies and perturbed hematopoiesis and perturbed hematopoiesis. Also, such a CAR product will always be specific for the individual patient. In contrast, NK cell infusions can be performed in non-HLA-matched settings due to the absence of alloreactivity of these innate immune cells. Still, the infused NK cells are subject to recognition and rejection by the patient\u2019s immune system, thereby limiting their life-span <jats:italic>in vivo<\/jats:italic> and undermining the possibility for multiple infusions. Here, we designed genome editing and advanced lentiviral transduction protocols to render primary human NK cells unsusceptible\/resistant to an allogeneic response by the recipient\u2019s CD8<jats:sup>+<\/jats:sup> T cells. After knocking-out surface expression of HLA class I molecules by targeting the B2M gene <jats:italic>via<\/jats:italic> CRISPR\/Cas9, we also co-expressed a single-chain HLA-E molecule, thereby preventing NK cell fratricide of B2M-knockout (KO) cells <jats:italic>via<\/jats:italic> \u201cmissing self\u201d-induced lysis. Importantly, these genetically engineered NK cells were functionally indistinguishable from their unmodified counterparts with regard to their phenotype and their natural cytotoxicity towards different AML cell lines. In co-culture assays, B2M-KO NK cells neither induced immune responses of allogeneic T cells nor re-activated allogeneic T cells which had been expanded\/primed using irradiated PBMNCs of the respective NK cell donor. Our study demonstrates the feasibility of genome editing in primary allogeneic NK cells to diminish their recognition and killing by mismatched T cells and is an important prerequisite for using non-HLA-matched primary human NK cells as readily available, \u201coff-the-shelf\u201d immune effectors for a variety of immunotherapy indications in human cancer.<\/jats:p>","DOI":"10.3389\/fimmu.2020.586168","type":"journal-article","created":{"date-parts":[[2021,1,29]],"date-time":"2021-01-29T05:42:00Z","timestamp":1611898920000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":53,"title":["HLA Class I Knockout Converts Allogeneic Primary NK Cells Into Suitable Effectors for \u201cOff-the-Shelf\u201d Immunotherapy"],"prefix":"10.3389","volume":"11","author":[{"given":"Keven","family":"Hoerster","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Uhrberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constanze","family":"Wiek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter A.","family":"Horn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helmut","family":"Hanenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Heinrichs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,1,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3390\/cells7100155","article-title":"Allogeneic CAR-T Cells: More than Ease of Access","volume":"7","author":"Graham","year":"2018","journal-title":"Cells"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.1957.tb05793.x","article-title":"Treatment of murine leukaemia with x-rays and homologous bone marrow. 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