Increase of Antitumoral Effects of Cytokine-Induced Killer Cells by Antibody-Mediated Inhibition of MICA Shedding

Abstract

<jats:p>Natural killer group 2D (NKG2D) receptor plays a pivotal role in cytokine-induced killer (CIK) cell-mediated cytotoxicity against malignancies, and the expression of NKG2D ligands might allow targets to be more susceptible to the CIK cell-mediated destruction. In this study, we investigated the synergistic effects of CIK cells antitumor activity and antibody-mediated inhibition of MICA/B shedding. This monoclonal antibody (7C6) has been previously shown to be able to specifically target MICA/B a3 domain on tumor cells, resulting in the increase in cell surface MICA/B expression by inhibition of their shedding. In the current study, we show that 7C6 antibody could substantially inhibit MICA shedding and stabilize the expression of MICA/B on Hela cells and MDA-MB-231 cells. In combination with 7C6, CIK cells showed higher degranulation rate, more IFN-γ production and elevated cytotoxic capacity against tumor cells. Furthermore, we demonstrate that NKG2D-MICA/B ligation could lead to activation of both CD3+ CD56− T cells and CD3+CD56+ NKT subset cells of CIK culture and NKT subset was more sensitive to NKG2D signaling than the counterpart T cells. 7C6-mediated inhibition of MICA shedding could strengthen this signal and eventually enhance the antitumor activity of CIK cells. With multiple advantages of easy ex vivo expansion, minor GVHD, natural tumor trafficking and non-MHC restricted, CIK cell-based therapy may serve as a potent combination partner with MICA antibody-mediated immunotherapy.</jats:p>

Technological Advancements in Monoclonal Antibodies

“…CD137 is a costimulating molecule that acts on the activation of T cells, regulating the activity of these cells in physiological and pathological processes [ 108 ]. Wang was one of the authors of a study that tested two types of mAbs for the treatment of hemophilia [ 109 ], and Zhang participated in a study whose objective was to evaluate the performance of monoclonal antibody 7C6 in marking MICA/B a3, a domain present in tumor cells, potentiating the activity of antitumor CIK cells [ 110 ]. Other studies of the main authors cited and other researchers are given in Table 3 .…”

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

“…Therefore, the strategy for preventing surface loss or upregulating the expression of NKG2D ligands may help to enhance the cytolytic ability of CIK cells against these tumors. We have previously shown that the cytotoxicity of CIK cells was enhanced by stabilization of MICA/B on tumor cells through selective small-molecule inhibitors or a specific anti-MICA monoclonal antibody (51,52). Furthermore, the ligands of NKG2D can be induced or upregulated by chemotherapeutic agents or radiation therapy (53,54); thus, the combination therapy of CIK cells with these traditional modalities might have synergistic benefits for cancer patients and further studies are needed in this regard.…”

PD‑1 blockade enhances cytokine‑induced killer cell‑mediated cytotoxicity in B‑cell non‑Hodgkin lymphoma cell lines

“…Approval of the ethics committee of the University Hospital Bonn was obtained, including signed informed consent from the volunteers. CIK cells were generated as previously described protocol ( 14 ). Briefly, a standard gradient density centrifugation using Pancoll (Pan-Biotech) was performed.…”