Abstract
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.
Highlights
Cytokine-induced killer (CIK) cells, as ex vivo expanded lymphocytes generated from peripheral blood mononuclear cells (PBMCs) in the presence of a cocktail of stimuli (IFN-g, anti-CD3 antibody, IL-2, IL-1b), were first introduced by Ingo Schmidt-Wolf and colleagues in 1991 [1]
As it was previously described that the majority of CD3+CD56+ cytotoxic cells in CIK cultures were derived from CD3+CD56− T cells [3], we focused mainly on CD3+CD56− T cells and detected the expression of both natural killer group 2D (NKG2D) (36.9%) and 2B4 (21.0%) (Figure 1A)
We investigated the role of NKG2D and 2B4 individually or in combination in CIK cell-related activities
Summary
Cytokine-induced killer (CIK) cells, as ex vivo expanded lymphocytes generated from peripheral blood mononuclear cells (PBMCs) in the presence of a cocktail of stimuli (IFN-g, anti-CD3 antibody, IL-2, IL-1b), were first introduced by Ingo Schmidt-Wolf and colleagues in 1991 [1]. After 14–21 days of expansion, CIK cells become a heterogeneous population of lymphocytes composed of a majority of CD3+CD56− T cells and CD3+CD56+ cells and a minor fraction of CD3−CD56+ natural killer (NK) cells [2]. Under this culture condition, the CD3+CD56+ subset is primarily derived from CD3+CD56− T cells and can be enriched in large numbers with great cytotoxicity [3]. Merker et al reported that CIK cell therapy induced a higher complete remission (CR) rate in patients with relapsing hematological malignancies after allogeneic HSCTs than donor-derived lymphocyte infusion (DLI) (53% and 29%, respectively), while relapse occurred in 47% and 71%, respectively [13]. No concurrent salvage therapies were used in this study, which could probably better interpret the efficacy of CIK cell therapy
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