Nature communications · 2024
CRISPR/Cas9 editing of NKG2A improves the efficacy of primary CD33-directed chimeric antigen receptor natural killer cells.
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Bexte Tobias, Albinger Nawid, Al Ajami Ahmad, Wendel Philipp, Buchinger Leon, Gessner Alec, Alzubi Jamal, Särchen Vinzenz, Vogler Meike, Rasheed Hadeer Mohamed, Jung Beate Anahita, Wolf Sebastian, Bhayadia Raj, Oellerich Thomas, Klusmann Jan-Henning, Penack Olaf, Möker Nina, Cathomen Toni, Rieger Michael A, Imkeller Katharina, Ullrich Evelyn
Аннотация
Chimeric antigen receptor (CAR)-modified natural killer (NK) cells show antileukemic activity against acute myeloid leukemia (AML) in vivo. However, NK cell-mediated tumor killing is often impaired by the interaction between human leukocyte antigen (HLA)-E and the inhibitory receptor, NKG2A. Here, we describe a strategy that overcomes CAR-NK cell inhibition mediated by the HLA-E-NKG2A immune checkpoint. We generate CD33-specific, AML-targeted CAR-NK cells (CAR33) combined with CRISPR/Cas9-based gene disruption of the NKG2A-encoding KLRC1 gene. Using single-cell multi-omics analyses, we identified transcriptional features of activation and maturation in CAR33-KLRC1ko-NK cells, which are preserved following exposure to AML cells. Moreover, CAR33-KLRC1ko-NK cells demonstrate potent antileukemic killing activity against AML cell lines and primary blasts in vitro and in vivo. We thus conclude that NKG2A-deficient CAR-NK cells have the potential to bypass immune suppression in AML.