In:
Frontiers in Immunology, Frontiers Media SA, Vol. 12 ( 2022-1-4)
Abstract:
The generation and expansion of functionally competent NK cells in vitro is of great interest for their application in immunotherapy of cancer. Since CD33 constitutes a promising target for immunotherapy of myeloid malignancies, NK cells expressing a CD33-specific chimeric antigen receptor (CAR) were generated. Unexpectedly, we noted that CD33-CAR NK cells could not be efficiently expanded in vitro due to a fratricide-like process in which CD33-CAR NK cells killed other CD33-CAR NK cells that had upregulated CD33 in culture. This upregulation was dependent on the stimulation protocol and encompassed up to 50% of NK cells including CD56 dim NK cells that do generally not express CD33 in vivo . RNAseq analysis revealed that upregulation of CD33 + NK cells was accompanied by a unique transcriptional signature combining features of canonical CD56 bright (CD117 high , CD16 low ) and CD56 dim NK cells (high expression of granzyme B and perforin). CD33 + NK cells exhibited significantly higher mobilization of cytotoxic granula and comparable levels of cytotoxicity against different leukemic target cells compared to the CD33 − subset. Moreover, CD33 + NK cells showed superior production of IFNγ and TNFα, whereas CD33 − NK cells exerted increased antibody-dependent cellular cytotoxicity (ADCC). In summary, the study delineates a novel functional divergence between NK cell subsets upon in vitro stimulation that is marked by CD33 expression. By choosing suitable stimulation protocols, it is possible to preferentially generate CD33 + NK cells combining efficient target cell killing and cytokine production, or alternatively CD33 − NK cells, which produce less cytokines but are more efficient in antibody-dependent applications.
Type of Medium:
Online Resource
ISSN:
1664-3224
DOI:
10.3389/fimmu.2021.798087
DOI:
10.3389/fimmu.2021.798087.s001
Language:
Unknown
Publisher:
Frontiers Media SA
Publication Date:
2022
detail.hit.zdb_id:
2606827-8
