Enhancement of tumor cell susceptibility to natural killer cell activity through inhibition of the PI3K signaling pathway

Natural killer (NK) cells are the primary effectors of the innate immune response against virus-infected cells or cells that have undergone malignant transformation. NK cells recognize their targets through a complex array of activating and inhibitory receptors, which regulate the intensity of the effector response against individual target cells. However, many studies have shown that tumor cells can escape immune cell recognition through a variety of mechanisms, developing resistance to NK cell killing. Using a lentiviral shRNA library, we previously demonstrated that several common signaling pathways modulate susceptibility of tumor cells to NK cell activity. In this study, we focused on one of the genes (PI3KCB), identified in this genetic screen. The PI3KCB gene encodes an isoform of the catalytic subunit of PI3K called P110 beta. The PI3K pathway has been linked to diverse cellular functions, but has never been associated with susceptibility to NK cell activity. Gene silencing of PI3KCB resulted in increased susceptibility of several tumor cell lines to NK cell lytic activity and induced increased IFN-gamma secretion by NK cells. Treatment of primary tumor cells with two different PI3K inhibitors also increased target cell susceptibility to NK cell activity. These effects are due, at least in part, to modulation of several activating and inhibitory ligands and appear to be correlated with PI3K signaling pathway inhibition. These findings identify a new and important role of PI3KCB in modulating tumor cell susceptibility to NK cells and open the way to future combined target immunotherapies.