Abstract
Natural killer (NK) cells are innate lymphocytes with a strong antitumor ability. In tumor patients, such as multiple myeloma (MM) patients, an elevated number of NK cells after stem cell transplantation (SCT) has been reported to be correlated with a higher overall survival rate. With the aim of improving NK cell use for adoptive cell therapy, we also addressed the cytotoxicity of patient-derived, cytokine-stimulated NK cells against MM cells at specific time points: at diagnosis and before and after autologous stem cell transplantation. Remarkably, after cytokine stimulation, the patients' NK cells did not significantly differ from those of healthy donors. In a small cohort of MM patients, we were able to isolate autologous tumor cells, and we could demonstrate that IL-2/15 stimulated autologous NK cells were able to significantly improve their killing capacity of autologous tumor cells. With the aim to further improve the NK cell killing capacity against MM cells, we investigated the potential use of NK specific check point inhibitors with focus on NKG2A because this inhibitory NK cell receptor was upregulated following ex vivo cytokine stimulation and MM cells showed HLA-E expression that could even be increased by exposure to IFN-γ. Importantly, blocking of NKG2A resulted in a significant increase in the NK cell-mediated lysis of different MM target cells. Finally, these results let suggest that combining cytokine induced NK cell activation and the specific check point inhibition of the NKG2A-mediated pathways can be an effective strategy to optimize NK cell therapeutic approaches for treatment of multiple myeloma.
Highlights
Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells (PCs)
The specific lysis of patient Natural killer (NK) cells in resting conditions was approximately 10% against all three cell lines, with a trend toward reduced cytotoxic capacity compared to healthy donors (HD) NK cells
These analyses show no significant differences in the killing activity of patient bone marrow (BM) and peripheral blood (PB) NK cells
Summary
Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells (PCs). The hallmarks of the disease are an excess of monoclonal PCs in combination with monoclonal protein in the blood and/or urine [1]. Standard therapy typically involves autologous stem cell transplantation (autoSCT) after induction, followed by high-dose chemotherapy treatment [2]. Given the risk of the treatment and its side effect, autoSCT is usually recommended only for youngest patients, accounting for approximately 30–40% of the patients with MM. Significant advances have been made in the treatment of MM by a combination of standard chemotherapy plus novel immunomodulatory drugs (IMiDs) or proteasome inhibitors, such as lenalidomide or bortezomib [4]
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