title: Transmissible cytotoxicity of multiple myeloma cells by cord blood-derived NK cells is mediated by vesicle trafficking.
abstract: 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.
authors.affiliation: 1] Department of Stem Cell Transplantation and Cellular Therapy, The University of Texs M.D. Anderson Cancer Center, Houston, TX, USA [2] Department of Hematology, Hospital Clinic, IDIBAPS, Josep Carreras Leukaemia Research Institute/University of Barcelona, Barcelona, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Martin-Antonio
authors.affiliation: Department of Cancer Systems Imaging, The University of Texs M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: Najjar
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texs M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: S N
authors.initials: SN
authors.lastname: Robinson
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texs M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: Chew
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texs M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texs M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: E
authors.initials: E
authors.lastname: Yvon
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texs M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: M W
authors.initials: MW
authors.lastname: Thomas
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texs M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: I
authors.initials: I
authors.lastname: Mc Niece
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: R
authors.initials: R
authors.lastname: Orlowski
authors.affiliation: Cell Death Regulation Group, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Muñoz-Pinedo
authors.affiliation: Josep Carreras Leukemia Research Institute and Cell Therapy Program of the School of Medicine, University of Barcelona, Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Bueno
authors.affiliation: 1] Josep Carreras Leukemia Research Institute and Cell Therapy Program of the School of Medicine, University of Barcelona, Barcelona, Spain [2] Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Menendez
authors.affiliation: Department of Hematology, Hospital Clinic, IDIBAPS, Josep Carreras Leukaemia Research Institute/University of Barcelona, Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Fernández de Larrea
authors.affiliation: Department of Hematology, Hospital Clinic, IDIBAPS, Josep Carreras Leukaemia Research Institute/University of Barcelona, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Urbano-Ispizua
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texs M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Shpall
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texs M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: N
authors.initials: N
authors.lastname: Shah
mesh_terms: D053148:Caspase 3 / Q000276:immunology; D005260:Female; D005312:Fetal Blood; D053804:Granzymes / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D008297:Male; D009101:Multiple Myeloma / Q000276:immunology* / Q000473:pathology; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology; D055628:Natural Cytotoxicity Triggering Receptor 3 / Q000276:immunology; D017382:Reactive Oxygen Species / Q000276:immunology; D022142:Secretory Vesicles / Q000276:immunology*
chemical_list: C527085:KLRK1 protein, human; C431710:NCR3 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055628:Natural Cytotoxicity Triggering Receptor 3; D017382:Reactive Oxygen Species; C509213:GZMB protein, human; D053804:Granzymes; C505407:CASP3 protein, human; D053148:Caspase 3