Oncoimmunology. 2022 May 31;11(1):2081415. doi: 10.1080/2162402X.2022.2081415. eCollection 2022.
ABSTRACT
Natural Killer (NK) cells are known for their high intrinsic cytotoxic capacity, and the possibility to be applied as ‘off-the-shelf’ product makes them highly attractive for cell-based immunotherapies. In patients with multiple myeloma (MM), an elevated number of NK cells has been correlated with higher overall-survival rate. However, NK cell function can be impaired by upregulation of inhibitory receptors, such as the immune checkpoint NKG2A. Here, we developed a CRISPR-Cas9-based gene editing protocol that allowed us to knockout about 80% of the NKG2A-encoding killer cell lectin like receptor C1 (KLRC1) locus in primary NK cells. In-depth phenotypic analysis confirmed significant reduction in NKG2A protein expression. Importantly, the KLRC1-edited NK cells showed significantly increased cytotoxicity against primary MM cells isolated from a small cohort of patients, and maintained the NK cell-specific cytokine production. In conclusion, KLRC1-editing in primary NK cells has the prospect of overcoming immune checkpoint inhibition in clinical applications.
PMID:35694192 | PMC:PMC9176243 | DOI:10.1080/2162402X.2022.2081415