Enhancing the activation and releasing the brakes : a double hit strategy to improve NK cell cytotoxicity against multiple myeloma

  • Natural killer (NK) cells are innate lymphocytes with a strong antitumor ability. In tumor patients, such as multiple myeloma (MM) patients, an elevated number of NK cells after stem cell transplantation (SCT) has been reported to be correlated with a higher overall survival rate. With the aim of improving NK cell use for adoptive cell therapy, we also addressed the cytotoxicity of patient-derived, cytokine-stimulated NK cells against MM cells at specific time points: at diagnosis and before and after autologous stem cell transplantation. Remarkably, after cytokine stimulation, the patients' NK cells did not significantly differ from those of healthy donors. In a small cohort of MM patients, we were able to isolate autologous tumor cells, and we could demonstrate that IL-2/15 stimulated autologous NK cells were able to significantly improve their killing capacity of autologous tumor cells. With the aim to further improve the NK cell killing capacity against MM cells, we investigated the potential use of NK specific check point inhibitors with focus on NKG2A because this inhibitory NK cell receptor was upregulated following ex vivo cytokine stimulation and MM cells showed HLA-E expression that could even be increased by exposure to IFN-γ. Importantly, blocking of NKG2A resulted in a significant increase in the NK cell-mediated lysis of different MM target cells. Finally, these results let suggest that combining cytokine induced NK cell activation and the specific check point inhibition of the NKG2A-mediated pathways can be an effective strategy to optimize NK cell therapeutic approaches for treatment of multiple myeloma.

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Author:Sara Tognarelli, Sebastian Wirsching, Ivana von Metzler, Bushra Rais, Benedikt Jacobs, Hubert ServeORCiDGND, Peter BaderORCiDGND, Evelyn UllrichORCiDGND
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/30542346
Parent Title (English):Frontiers in immunology
Publisher:Frontiers Media
Place of publication:Lausanne
Contributor(s):Nicola Giuliani
Document Type:Article
Year of Completion:2018
Date of first Publication:2018/11/27
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2019/03/05
Tag:NK cells; NKG2A blocking; adoptive cell therapy; autologous stem cell transplantation; checkpoint inhibition; multiple myeloma
Issue:Art. 2743
Page Number:15
First Page:1
Last Page:15
Copyright © 2018 Tognarelli, Wirsching, von Metzler, Rais, Jacobs, Serve, Bader and Ullrich. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0