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

Xiaolong Wu,Ingo G.H Schmidt-Wolf,Ying Zhang,Yutao Li

doi:10.3390/cancers12071818

Abstract

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.

Highlights

Immunotherapy is emerging as a revolution in cancer treatment
After 14 days of ex vivo expansion, the bulk cytokine-induced killer (CIK) cells were a heterogeneous population composed by CD3+CD56+ “NKT” cells (31.3% ± 11.2%), CD3+CD56− T cells (65.6% ± 8.9%), and a small percentage of CD3-CD56+ NK cells (2.8% ± 4.4%) (Figure 1A, one representative data of four donors)
Cells and T cells were the main cells with Natural killer group 2D (NKG2D) expression

Summary

Introduction

Chimeric antigen receptor (CAR)-T cell therapy has shown clinical success in the treatment of certain blood cancers and has been approved by the FDA. This therapy is so far limited in hematological malignancies with potentially fatal treatment-related side effects, such as cytokine release syndrome (CRS) and neurotoxicity. With a broad antitumor spectrum, CIK cells have been shown to have therapeutic effect in patients with both hematological and solid cancers [2,3]. Due to the easy ex vivo expansion, minor GVHD, natural tumor trafficking and non-MHC restricted, intensive attempts have been made in an effort to improve the therapeutic efficacy of CIK cells in both basic and clinical research since its first report [4,5,6,7,8]

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