Transmissible cytotoxicity of multiple myeloma cells by cord blood-derived NK cells is mediated by vesicle trafficking

• Published in: Cell death and differentiation Vol. 22; no. 1; pp. 96 - 107
• Main Authors: Martin-Antonio, B, Najjar, A, Robinson, S N, Chew, C, Li, S, Yvon, E, Thomas, M W, Mc Niece, I, Orlowski, R, Muñoz-Pinedo, C, Bueno, C, Menendez, P, Fernández de Larrea, C, Urbano-Ispizua, A, Shpall, E J, Shah, N
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2015; Nature Publishing Group
• Subjects: 631/67/1990/804; 631/67/580; 631/80/313; 631/80/82; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cancer; Caspase 3 - immunology; Cell Biology; Cell Cycle Analysis; Cell death; Cytotoxicity; Endoplasmic reticulum; Female; Fetal Blood; Granzymes - immunology; Hematology; Humans; Immunity, Cellular; K562 Cells; Killer Cells, Natural - immunology; Killer Cells, Natural - pathology; Leukemia; Life Sciences; Ligands; Male; Multiple myeloma; Multiple Myeloma - immunology; Multiple Myeloma - pathology; Natural Cytotoxicity Triggering Receptor 3 - immunology; NK Cell Lectin-Like Receptor Subfamily K - immunology; Original Paper; Ovaries; Plasma; Proteins; Reactive Oxygen Species - immunology; Research centers; Secretory Vesicles - immunology; Stem Cells; United States > US; Spain
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2014.120

Natural killer cells (NK) are important effectors of anti-tumor immunity, activated either by the downregulation of HLA-I molecules on tumor cells and/or the interaction of NK-activating receptors with ligands that are overexpressed on target cells upon tumor transformation (including NKG2D and NKP30). NK kill target cells by the vesicular delivery of cytolytic molecules such as Granzyme-B and Granulysin activating different cell death pathways, which can be Caspase-3 dependent or Caspase-3 independent. Multiple myeloma (MM) remains an incurable neoplastic plasma-cell disorder. However, we previously reported the encouraging observation that cord blood-derived NK (CB-NK), a new source of NK, showed anti-tumor activity in an in vivo murine model of MM and confirmed a correlation between high levels of NKG2D expression by MM cells and increased efficacy of CB-NK in reducing tumor burden. We aimed to characterize the mechanism of CB-NK-mediated cytotoxicity against MM cells. We show a Caspase-3- and Granzyme-B-independent cell death, and we reveal a mechanism of transmissible cell death between cells, which involves lipid–protein vesicle transfer from CB-NK to MM cells. These vesicles are secondarily transferred from recipient MM cells to neighboring MM cells amplifying the initial CB-NK cytotoxicity achieved. This indirect cytotoxicity involves the transfer of NKG2D and NKP30 and leads to lysosomal cell death and decreased levels of reactive oxygen species in MM cells. These findings suggest a novel and unique mechanism of CB-NK cytotoxicity against MM cells and highlight the importance of lipids and lipid transfer in this process. Further, these data provide a rationale for the development of CB-NK-based cellular therapies in the treatment of MM.