| Autor: |
Tobias Bexte, Nawid Albinger, Ahmad Al Ajami, Philipp Wendel, Leon Buchinger, Alec Gessner, Jamal Alzubi, Vinzenz Särchen, Meike Vogler, Hadeer Mohamed Rasheed, Beate Anahita Jung, Sebastian Wolf, Raj Bhayadia, Thomas Oellerich, Jan-Henning Klusmann, Olaf Penack, Nina Möker, Toni Cathomen, Michael A. Rieger, Katharina Imkeller, Evelyn Ullrich |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
Nature Communications, Vol 15, Iss 1, Pp 1-19 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2041-1723 |
| DOI: |
10.1038/s41467-024-52388-1 |
| Popis: |
Abstract 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-KLRC1 ko-NK cells, which are preserved following exposure to AML cells. Moreover, CAR33-KLRC1 ko-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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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