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J Immunother Cancer. 2019 Oct 16;7(1):259. doi: 10.1186/s40425-019-0739-1.

Extracellular NK histones promote immune cell anti-tumor activity by inducing cell clusters through binding to CD138 receptor.

Author information

1
Department of Hematology, Hospital Clinic, IDIBAPS, Carrer Rosselló 149-153, 08036, Barcelona, Spain. bmartina@clinic.cat.
2
Josep Carreras Leukaemia Research Institute, Carrer Rosselló 149-153, 08036, Barcelona, Spain. bmartina@clinic.cat.
3
Department of Hematology, Hospital Clinic, IDIBAPS, Carrer Rosselló 149-153, 08036, Barcelona, Spain.
4
Josep Carreras Leukaemia Research Institute, Carrer Rosselló 149-153, 08036, Barcelona, Spain.
5
Department of Pediatrics - Research, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
6
Immunoreceptors of the Innate and Adaptive System Group, IDIBAPS, Barcelona, Spain.
7
Department of Immunology, Hospital Clinic of Barcelona, Barcelona, Spain.
8
Department of Biomedical Sciences, School of Medicine, University of Barcelona, Barcelona, Spain.
9
Josep Carreras Leukemia Research Institute and Cell Therapy Program of the School of Medicine, University of Barcelona, Barcelona, Spain.
10
Proteomic department, University of Barcelona, Barcelona, Spain.
11
Cell Death Regulation Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
12
Department of Stem Cell Transplantation & Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
13
Department of Hematology, University of Barcelona, Barcelona, Spain.

Abstract

BACKGROUND:

Natural killer (NK) cells are important anti-tumor cells of our innate immune system. Their anti-cancer activity is mediated through interaction of a wide array of activating and inhibitory receptors with their ligands on tumor cells. After activation, NK cells also secrete a variety of pro-inflammatory molecules that contribute to the final immune response by modulating other innate and adaptive immune cells. In this regard, external proteins from NK cell secretome and the mechanisms by which they mediate these responses are poorly defined.

METHODS:

TRANS-stable-isotope labeling of amino acids in cell culture (TRANS-SILAC) combined with proteomic was undertaken to identify early materials transferred between cord blood-derived NK cells (CB-NK) and multiple myeloma (MM) cells. Further in vitro and in vivo studies with knock-down of histones and CD138, overexpression of histones and addition of exogenous histones were undertaken to confirm TRANS-SILAC results and to determine functional roles of this material transferred.

RESULTS:

We describe a novel mechanism by which histones are actively released by NK cells early after contact with MM cells. We show that extracellular histones bind to the heparan sulfate proteoglycan CD138 on the surface of MM cells to promote the creation of immune-tumor cell clusters bringing immune and MM cells into close proximity, and thus facilitating not only NK but also T lymphocyte anti-MM activity.

CONCLUSION:

This study demonstrates a novel immunoregulatory role of NK cells against MM cells mediated by histones, and an additional role of NK cells modulating T lymphocytes activity that will open up new avenues to design future immunotherapy clinical strategies.

KEYWORDS:

Cell-cell communication; Histones; Immunotherapy; Multiple myeloma; NK cells

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