| Autor: |
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 |
| Předmět: |
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| Zdroj: |
Nature Communications; 9/30/2024, Vol. 15 Issue 1, p1-19, 19p |
| Abstrakt: |
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. NK cell-based therapy can kill acute myeloid leukemia (AML), but immune suppression may occur. Here the authors overcome the immunosuppression of AML-targeted CAR33-NK cells via non-viral CRISPR-editing of the immune checkpoint NKG2A, leading to an enhanced potency of the CAR-NK cell product with sustained anti-tumor efficacy. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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