Augmented anti-tumor activity of NK-92 cells expressing chimeric receptors of TGF-βR II and NKG2D

The capacity of natural killer (NK) cells to kill tumor cells without specific antigen recognition provides an advantage over T cells and makes them potential effectors for tumor immunotherapy. However, the efficacy of NK cell adoptive therapy can be limited by the immunosuppressive tumor microenvironment. Transforming growth factor-beta (TGF-beta) is a potent immunosuppressive cytokine that can suppress NK cell function. To convert the suppressive signal induced by TGF-beta to an activating signal, we genetically modified NK-92 cells to express a chimeric receptor with TGF-beta type II receptor extracellular and transmembrane domains and the intracellular domain of NK cell-activating receptor NKG2D (TN chimeric receptor). NK-92 cells expressing TN receptors were resistant to TGF-beta-induced suppressive signaling and did not down-regulate NKG2D. These modified NK-92 cells had higher killing capacity and interferon gamma (IFN-gamma) production against tumor cells compared with the control cells and their cytotoxicity could be further enhanced by TGF-beta. More interestingly, the NK-92 cells expressing TN receptors were better chemo-attracted to the tumor cells expressing TGF-beta. The presence of these modified NK-92 cells significantly inhibited the differentiation of human na < ve CD4(+) T cells to regulatory T cells. NK-92-TN cells could also inhibit tumor growth in vivo in a hepatocellular carcinoma xenograft tumor model. Therefore, TN chimeric receptors can be a novel strategy to augment anti-tumor efficacy in NK cell adoptive therapy.