Blocking transforming growth factor-β signaling pathway augments antitumor effect of adoptive NK-92 cell therapy

Abstract

Natural killer (NK) cells hold great potential for improving the immunotherapy of cancer. However, existing data indicate that tumor cells can effectively escape NK cell-mediated apoptosis through immunosuppressive effect in the tumor microenvironment. Transforming growth factor-β (TGF-β) is a potent immunosuppressant. The present study was intended to develop a treatment strategy through adoptive transfer of TGF-β insensitive NK-92 cells. To block TGF-β signaling pathway, NK-92 cells were genetically modified with dominant negative TGF-β type II receptor (DNTβRII) by optimizing electroporation using the Amaxa Nucleofector system. These genetically modified NK-92 cells were insensitive to TGF-β and able to resist the suppressive effect of TGF-β on Calu-6 lung cancer cells in vitro. To determine the antitumor activity in vivo, recipient mice were challenged with a single subcutaneous injection of Calu-6 cells. Adoptive transfer of TGF-β insensitive NK-92 cells decreased tumor proliferation, reduced lung metastasis, produced more IFN-γ, and increased the survival rate of nude mice bearing established Calu-6 cells. Hence, we have demonstrated that blocking transforming growth factor-β signaling pathway in NK cells provides a novel therapeutic strategy and warrants further investigation.