Novel strategies to target cancer stem cells by NK cells; studies in humanized mice.

We have previously shown, that following selection, natural killer (NK) cells differentiate cancer stem-like cells (CSCs)/poorly differentiated tumors via secreted and membrane bound IFN-gamma and TNF-alpha, leading to prevention of tumor growth and remodeling of the tumor microenvironment. Since conventional therapeutic strategies, including chemotherapy and radiotherapy remain unsuccessful in treating stem-like tumors, there has been increasing interest in NK cell-targeted immunotherapy for the treatment of aggressive malignacies. In our recent studies, we used a humanized (hu-BLT) mouse model with transplanted human bone marrow, liver and thymus to demonstrate the efficacy of adoptive transfer of ex vivo expanded, super-charged NK cells in selection and differentiation of stem-like tumors within the context of a fully reconstituted human immune system. We have also shown that CSCs differentiated with split anergized NK cells prior to implantation in humanized mice did not grow or metastasize. In this review, we present current advances in NK cell detection, expansion and therapeutic delivery methods, and discuss the utility of different humanized mouse models in studying NK cell-based therapies in the preclinical setting.