Anti‐myeloma activity of natural killer lymphocytes

Abstract

Summary. Natural killer (NK) cells are assumed to contribute to a graft-versus-leukaemia effect. In vitro experiments have shown that many leukaemic cells are NK-cell sensitive. Nevertheless, no data concerning the influence of purified NK cells on malignant myeloma (MM) cells exist. We co-incubated NK cells with three different MM cell lines and fresh bone marrow samples of nine MM patients. The proportion of vital MM cells was determined before and after co-cultivation by a flow-cytometry-based assay. All MM cells tested, with the exception of one cell line (NCI H929), were susceptible to a NK-cell attack even without exogenous interleukin 2 (IL-2). The mean killing of the native MM samples was 23AE1 ± 5AE4% and 34AE5 ± 6AE5% at 10:1 and 20:1 effector:target ratio respectively, This corresponded to about 2/3 of those values obtained with the highly sensitive line K562. In contrast, CD34-positive haematopoietic stem cells as well as peripheral mononuclear cells were completely resistant under similar experimental conditions (1AE3% killing). To elucidate the underlying triggering mechanisms, we measured human leucocyte antigen (HLA)-class I expression of the MM cells. No evidence for HLA loss, which could have explained the NK-cell recognition if it occurred, was demonstrated. These findings may contribute to the understanding of in vivo NK-cell activation and encourage clinical applications of NK cells for MM patients.

Bortezomib significantly impairs the immunostimulatory capacity of human myeloid blood dendritic cells

“…48 Recent studies revealed the capability of human DCs to promote NK cell proliferation, IFN-g-secretion and tumor-directed cytotoxicity. 15,49,50 Following our observation that slanDCs can also efficiently trigger NK cells 34,44 and previous reports demonstrating effective NK cell-mediated lysis of myeloma cells, 51,52 we determined whether bortezomib influences the capability of slanDCs to activate these innate effector cells. Therefore, bortezomib-pretreated DCs were cocultured with immunomagnetically purified autologous CD56 þ CD3À NK cells in the presence of LPS for 18 h. As demonstrated in Figure 5, bortezomib significantly reduced the ability of LPS-activated slanDCs to improve IFN-g production by NK cells.…”

“…Labeled target cells were plated as triplicates in round-bottomed 96-well plates at 5 Â 10 3 per well and incubated with NK cells at an effector (E)-to-target (T) cell ratio of 20:1. After 4 h, 51 Cr release was determined in a beta counter.…”

Natural killer cell lines preferentially kill clonogenic multiple myeloma cells and decrease myeloma engraftment in a bioluminescent xenograft mouse model

“…[11][12][13][14][15] Allogeneic hematopoietic cell transplantation is controversial in MM and often associated with high mortality, due in part to increased rates and severity of graft-versus-host disease (GvHD). 16 However, increased survival was shown for MM patients undergoing HLA-matched sibling hematopoietic cell transplantation after initial autologous transplantation compared to patients receiving tandem autologous transplants.…”

Inhibition of Glycogen Synthase Kinase-3 Increases NKG2D Ligand MICA Expression and Sensitivity to NK Cell–Mediated Cytotoxicity in Multiple Myeloma Cells: Role of STAT3

“…MM is an incurable disease with a median survival of a few years, recently improved by the introduction of new antimyeloma chemotherapeutic agents such as bortezomib and thalidomide/lenalidomide, and by the wider use of transplant procedures (7)(8)(9), in which part of the curative potential of allografts is attributed to a graft-versus-tumor effect mediated by donor lymphocytes (10,11). In this regard, a number of evidences in myeloma patients strongly support the antitumor potential of NK cells in response to immunomodulatory drugs or following allogeneic stem cell transplantation (12)(13)(14), and several studies have shown that the engagement of the NKG2D and DNAX accessory molecule-1 (DNAM-1)-activating receptors plays an important role in the recognition and killing of MM cells by NK cells (15)(16)(17). Indeed, MM cells can express the NKG2D ligands MICA/B (15,18), different UL16-binding proteins, and the DNAM1-ligands poliovirus receptor (PVR; CD155) and nectin-2 (19,20).…”