Antibody-Dependent Cellular Cytotoxicity of iPS Cell-Derived Natural Killer T Cells by Anti-GD2 mAb for Neuroblastoma

Abstract

While antibody-dependent cellular cytotoxicity (ADCC) by anti-disialoganglioside GD2 monoclonal antibody (mAb) has succeeded in increasing the survival rate of high-risk patients with neuroblastoma, approximately 40%–50% of patients die from the disease. Recently, we developed induced pluripotent stem cell-derived natural killer T (iPS-NKT) cells, which exhibit NK-like cytotoxicity. However, whether iPS-NKT cells can induce ADCC function is unclear. Here, we investigated the ADCC of iPS-NKT cells and the efficacy of the combination treatment of anti-GD2 mAb and iPS-NKT cells against neuroblastoma. Anti-GD2 mAb enhanced the cytotoxicity and secretion of cytokines and cytotoxic granules of iPS-NKT cells, which expressed CD16 to GD2-expressing neuroblastoma cell lines. We also examined which Fcγ receptors contribute to ADCC of iPS-NKT cells. CD16 stimulation against iPS-NKT cells caused cytotoxicity and secretion of interferon-gamma, tumor necrosis factor, and granzyme B. In contrast, CD32 and CD64 stimulation did not. In vivo, the intratumor administration of anti-GD2 mAb and iPS-NKT cells significantly inhibited tumor growth compared with the other treatment groups: no treatment, anti-GD2 mAb alone, and iPS-NKT cells alone. In conclusion, iPS-NKT cells exhibit CD16-mediated ADCC, and the addition of iPS-NKT cells to anti-GD2 mAb therapy may be a potential approach for immunotherapy against neuroblastoma.