CD33 Delineates Two Functionally Distinct NK Cell Populations Divergent in Cytokine Production and Antibody-Mediated Cellular Cytotoxicity.

The generation and expansion of functionally competent NK cells 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 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 NK cells that do generally not express CD33 . RNAseq analysis revealed that upregulation of CD33 NK cells was accompanied by a unique transcriptional signature combining features of canonical CD56 (CD117, CD16) and CD56 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 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.

Copyright © 2022 Hejazi, Zhang, Bennstein, Balz, Reusing, Quadflieg, Hoerster, Heinrichs, Hanenberg, Oberbeck, Nitsche, Cramer, Pfeifer, Oberoi, Rühl, Oldenburg, Brossart, Horn, Babor, Wels, Fischer, Möker and Uhrberg.

PMID: 35058934