Natural Killer (NK) cells in multiple myeloma are dysfunctional. We explored the mechanism by which this occurs in samples from newly diagnosed (NDMM) and refractory relapse multiple myeloma (RRMM) patients. Using in vitro assays and gene expression analysis, we investigated MM patient peripheral blood NK cell phenotypes, differentiation, and effector functions. We also explored the best timepoint in MM patient treatment to apply NK-focussed immunotherapy.
NK cells from MM patients had skewed differentiation with an accumulation of terminally differentiated CD57+ NK cells and an imbalance of activating and inhibitory receptors compared to healthy individuals. These CD57+ NK cells expressed high levels of effector proteins perforin and granzyme B. Despite this, MM patient NK cells were hypo-responsive to activation via CD16a. Importantly, gene expression analysis revealed pathways regulating activation and differentiation were downregulated in CD57+ MM NK cells compared to healthy donor NK cells indicating the mechanism for their apparent hyporesponsive state. We then explored whether autologous stem cell transplantation (ASCT) rescued this MM patient NK cell dysfunction. We examined NK cell effector functions pre- and post-ASCT and noted that post-ASCT NK cell cytotoxic function was impaired suggesting that, in MM patients, NK cell maturation in the bone marrow post-ASCT is affected by the presence of residual myeloma cells.
In conclusion, we showed that the mechanisms for NK cell dysfunction in MM include skewed differentiation with an imbalance of activating:inhibitory receptors and significantly reduced activation signaling responses. MM patient NK cells should be targeted after immunomodulatory induction or at an early stage.