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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.

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