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NKG2D Engagement Alone Is Sufficient to Activate Cytokine-Induced Killer Cells While 2B4 Only Provides Limited Coactivation

  • Cytokine-induced killer (CIK) cells are an ex vivo expanded heterogeneous cell population with an enriched NK-T phenotype (CD3+CD56+). Due to the convenient and relatively inexpensive expansion capability, together with low incidence of graft versus host disease (GVHD) in allogeneic cancer patients, CIK cells are a promising candidate for immunotherapy. It is well known that natural killer group 2D (NKG2D) plays an important role in CIK cell-mediated antitumor activity; however, it remains unclear whether its engagement alone is sufficient or if it requires additional co-stimulatory signals to activate the CIK cells. Likewise, the role of 2B4 has not yet been identified in CIK cells. Herein, we investigated the individual and cumulative contribution of NKG2D and 2B4 in the activation of CIK cells. Our analysis suggests that (a) NKG2D (not 2B4) is implicated in CIK cell (especially CD3+CD56+ subset)-mediated cytotoxicity, IFN-γ secretion, E/T conjugate formation, and degranulation; (b) NKG2D alone is adequate enough to induce degranulation, IFN-γ secretion, and LFA-1 activation in CIK cells, while 2B4 only provides limited synergy with NKG2D (e.g., in LFA-1 activation); and (c) NKG2D was unable to costimulate CD3. Collectively, we conclude that NKG2D engagement alone suffices to activate CIK cells, thereby strengthening the idea that targeting the NKG2D axis is a promising approach to improve CIK cell therapy for cancer patients. Furthermore, CIK cells exhibit similarities to classical invariant natural killer (iNKT) cells with deficiencies in 2B4 stimulation and in the costimulation of CD3 with NKG2D. In addition, based on the current data, the divergence in receptor function between CIK cells and NK (or T) cells can be assumed, pointing to the possibility that molecular modifications (e.g., using chimeric antigen receptor technology) on CIK cells may need to be customized and optimized to maximize their functional potential.

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Document Type:Article
Author:Xiaolong Wu, Amit Sharma, Johannes Oldenburg, Hans Weiher, Markus Essler, Dirk Skowasch, Ingo G. H. Schmidt-Wolf
Parent Title (English):Frontiers in Immunology
Article Number:731767
Number of pages:12
Publisher:Frontiers Media SA
Publishing Institution:Hochschule Bonn-Rhein-Sieg
Date of first publication:2021/10/07
Copyright:Copyright © 2021 Wu, Sharma, Oldenburg, Weiher, Essler, Skowasch and Schmidt-Wolf. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).
Funding:The support of the Deutsche Krebshilfe (DKH), Bonn, Germany is kindly acknowledged.
Keyword:2B4; LFA-1; MICA/B; NKG2D; cytokine-induced killer (CIK) cells
Departments, institutes and facilities:Fachbereich Angewandte Naturwissenschaften
Institut für funktionale Gen-Analytik (IFGA)
Dewey Decimal Classification (DDC):6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Entry in this database:2021/10/13
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International