Differential killing of pre-B acute lymphoblastic leukaemia cells by activated NK cells and the NK-92 ci cell line

Abstract

SUMMARYThe use of NK cells in adoptive therapy for malignant disease is an area of great potential. Currently the only NK cell line in clinical trials is NK-92, an activated NK cell line with a broad range of cytotoxicity against malignant cells. The activity of NK-92 against pre-B acute lymphoblastic leukaemias, however, is highly variable. In this study we compare the cytotoxic mechanisms and signalling pathways utilized by NK-92 ci and IL-2 activated NK cells to mediate killing of pre-B acute lymphoblastic leukaemia cell lines. Deficiencies in TNF family mediated apoptosis, phosphoinositide-3 kinase dependent and phosphoinositide-3 kinase independent killing limit the efficiency of NK-92 ci against pre-B acute lymphoblastic leukaemia cells. Importantly, treatment of the poorly killed leukaemia cells with TNF-a augmented both phosphoinositide-dependent and -independent cytolysis.

Novel molecular and cellular therapeutic targets in acute lymphoblastic leukemia and lymphoproliferative disease

“…Indeed, T cells specific for epitopes derived from such proteins have been detected in leukemia patients [143,144], and have been shown to be capable of exerting significant anti-leukemia activity in xenograft models [145]. However, attempts to generate effective, sustained clinical anti-leukemia immune responses have been undermined by the immune subversion mechanisms present in patients at advanced stages of disease, including Th2 skewing [146], loss of costimulatory molecule expression on leukemia cells [147], dendritic cell dysfunction [148], and an insensitivity of leukemia cells to immune effector mechanisms [149,150].…”

NK cell receptors and their ligands in leukemia

“…Moreover, studies showed that leukemic blasts from B-ALL patients were more resistant to killing by the NK-92 cell line than the other types of leukemia. [47][48][49] It has also been demonstrated that the NK-92 cell line does not induce cytotoxicity toward normal bone marrow cells, suggesting that malignant hematopoietic cells express additional activating ligands and that resistance of certain leukemic cells could be caused by the absence or downregulated expression of these NK activating ligands. 47,50 In this regard, a study established that the NK-92 cell line could be used as a purging agent to decrease or eliminate the malignant contamination of autologous stem cell grafts in CML patients.…”

“…[47][48][49] The NK-92 cell line is an IL-2 dependent cell line isolated from a patient with non-Hodgkin's lymphoma at diagnosis. The high cytotoxicity of the NK-92 cell line is thought to be the result of an almost complete lack of inhibitory KIRs with a preserved perforin-and granzyme-mediated cytotoxicity.…”

Live cell evaluation of granzyme delivery and death receptor signaling in tumor cells targeted by human natural killer cells

“…50,51 Likewise, Fas is also expressed by Jurkat, 48,49 and reports have indicated killing by NK92. 52 To measure the effect of death receptor function on caspase biosensor activation in K562 cells, we incubated PRF NK cells is dependent on death receptor ligation, and highlights differing sensitivities of tumor cell lines to caspase activation after death receptor signaling.…”