Cord blood natural killer cells expressing a dominant negative TGF-β receptor: Implications for adoptive immunotherapy for glioblastoma

Abstract

Cord blood (CB) natural killer (NK) cells are promising effector cells for tumor immunotherapy but are currently limited by immune-suppressive cytokines in the tumor microenvironment, such as transforming growth factor (TGF-β). We observed that TGF-β inhibits expression of activating receptors such as NKG2D and DNAM1 and decreases killing activity against glioblastoma tumor cells through inhibition of perforin secretion. To overcome the detrimental effects of TGF-β, we engrafted a dominant negative TGF-β receptor II (DNRII) on CB-derived NK cells by retroviral transduction and evaluated their ability to kill glioblastoma cells in the presence of TGF-β. After manufacture using Good Manufacturing Practice-compliant methodologies and transduction with DNRII, CB-derived DNRII-transduced NK cells expanded to clinically relevant numbers and retained both their killing ability and their secretion of interferon-γ upon activation. More important, these cells maintained both perforin expression and NKG2D/DNMA1 expression in the presence of TGF-β allowing for recognition and killing of glioblastoma tumor cells. Hence, NK cells expressing a DNRII should have a functional advantage over unmodified NK cells in the presence of TGF-β-secreting tumors and may be an important therapeutic approach for patients with cancer.

Keywords: TGF-β; cord blood natural killer cells; dominant negative receptor; glioma; immunotherapy.