Natural killer (NK) cell-based immunotherapy is a promising novel approach to 
treat cancer. However, NK cell function has been shown to be potentially 
diminished by factors common in the tumor microenvironment (TME). In this study, 
we assessed the synergistic potential of antibody-dependent cell-mediated 
cytotoxicity (ADCC) and killer immunoglobin-like receptor (KIR)-ligand 
mismatched NK cells to potentiate NK cell antitumor reactivity in multiple 
myeloma (MM). Hypoxia, lactate, prostaglandin E2 (PGE2) or combinations were 
selected to mimic the TME. To investigate this, NK cells from healthy donors 
were isolated and NK cell ADCC capacity in response to MM cells was assessed in 
flow cytometry-based cytotoxicity and degranulation (CD107a) assays in the 
presence of TME factors. Hypoxia, lactate and PGE2 reduced cytotoxicity of NK 
cells against myeloma target cells. The addition of daratumumab (anti-CD38 
antibody) augmented NK-cell cytotoxicity against target cells expressing high 
CD38, but not against CD38 low or negative target cells also in the presence of 
TME. Co-staining for inhibitory KIRs and NKG2A demonstrated that daratumumab 
enhanced degranulation of all NK cell subsets. Nevertheless, KIR-ligand 
mismatched NK cells were slightly better effector cells than KIR-ligand matched 
NK cells. In summary, our study shows that combination therapy using strategies 
to maximize activating NK cell signaling by triggering ADCC in combination with 
an approach to minimize inhibitory signaling through a selection of KIR-ligand 
mismatched donors, can help to overcome the NK-suppressive TME. This can serve 
as a platform to improve the clinical efficacy of NK cells.