Ehanced Nk Cell Adoptive Antitumor Effects Against Breast Cancer In Vitro Via Blockade Of The Transforming Growth Factor-Beta Signaling Pathway

Natural killer (NK) cells have great potential for improving cancer immunotherapy. Adoptive NK cell transfer, an adoptive immunotherapy, represents a promising nontoxic anticancer therapy. However, existing data indicate that tumor cells can effectively escape NK cell-mediated apoptosis through immunosuppressive effects in the tumor microenvironment, and the therapeutic activity of adoptive NK cell transfer is not as efficient as anticipated. Transforming growth factor-beta (TGF-beta ) is a potent immunosuppressant. Genetic and epigenetic events that occur during mammary tumorigenesis circumvent the tumor-suppressing activity of TGF-beta, thereby permitting late-stage breast cancer cells to acquire an invasive and metastatic phenotype in response to TGF-beta. To block the TGF-beta signaling pathway, NK cells were genetically modified with a dominant-negative TGF-beta type II receptor by optimizing electroporation using the Amaxa Nucleofector system. These genetically modified NK cells were insensitive to TGF-beta and resisted the suppressive effect of TGF-beta on MCF-7 breast cancer cells in vitro. Our results demonstrate that blocking the TGF-beta signaling pathway to modulate the tumor microenvironment can improve the antitumor activity of adoptive NK cells in vitro, thereby providing a new rationale for the treatment of breast cancer.