Adaptive Natural Killer Cells Facilitate Effector Functions of Daratumumab in Multiple Myeloma

Abstract

Purpose: To investigate the different roles of heterogeneous natural killer (NK) cell subpopulations in multiple myeloma (MM) and to identify NK cell subsets that support the robust anti-myeloma activity of daratumumab via antibody-dependent cellular cytotoxicity (ADCC). Experimental design: We performed single-cell RNA sequencing of NK cells from newly diagnosed MM (NDMM) patients and delineated adaptive NK cells in their bone marrow (BM). We further characterized the distinct immunophenotypic features and functions of adaptive NK cells by multicolor flow cytometry in 157 NDMM patients. Results: Adaptive NK cells exhibit a significantly lower level of CD38 expression compared with conventional NK cells, suggesting that they may evade daratumumab-induced fratricide. Moreover, adaptive NK cells exert robust daratumumab-mediated effector functions ex vivo, including cytokine production and degranulation, compared with conventional NK cells. The composition of adaptive NK cells in BM determines the daratumumab-mediated ex vivo functional activity of BM NK cells in NDMM patients. Unlike conventional NK cells, sorted adaptive NK cells from the BM of NDMM patients exert substantial cytotoxic activity against myeloma cells in the presence of daratumumab. Conclusions: Our findings indicate that adaptive NK cells are an important mediator of ADCC in MM and support direct future efforts to better predict and improve the treatment outcome of daratumumab by selectively employing adaptive NK cells.