Potential Cancer Prevention and Treatment by Silencing the Killer Cell Immunoglobulin-like Receptor Gene in Natural Killer Cells Derived from Induced Pluripotent Stem Cells.

Cancer immunosurveillance is an important host protection process, monitoring the presence of irregular cells that could potentially transform into tumor cells, effectively clearing the body of transformed tumor cells at their earliest stages, and thus maintaining regular cellular homeostasis. Natural killer (NK) cells are effector lymphocytes of the innate immune system, playing a critical role in surveillance for tumor cells, while also eliminating virally infected cells. The significance of the anti-tumor role of NK cells was recently further verified by findings that immunosuppression in most cancer patients is not perceptible until late stages. NK cells express the low-affinity Fc-activating receptor, CD16, and the inhibitory receptor, killer cell immunoglobulin-like receptor (KIR). Consequently, activation of NK cells is determined by the balance of inhibitory and activating receptor stimulation. Here, we propose establishing an induced pluripotent stem cell (iPSC)-derived NK cell line with KIR gene knockout or knockdown as a possible regimen to treat and prevent cancer. We further postulate that an optimal mixture of NK iPSCs with and without KIR gene knockout, would reach a maximum antitumor activity, with minimal side effects. We also discuss the possible advantages of KIR-knockout NK iPSCs for adoptive immunotherapy in patients with cancer.