Novel strategies to expand supercharged NK cells with augmented capacity to withstand inactivation by tumors

Natural killer (NK) cells are the main immune effectors with the ability to mediate selection and differentiation of a number of different cancer stem cells/undifferentiated or poorly differentiated tumors via lysis, and secreted or membrane bound IFN-γ and TNF-α. Tumor differentiation by NK cells leads to growth inhibition and curtailment of tumor metastasis. In this chapter, we present an overview of our recent and past findings on the biology and significance of NK cells in the selection/differentiation of stem-like tumors using in vitro and in vivo studies conducted in the NSG and humanized-BLT mice and those of cancer patients. In addition, we discuss the significance of heightened NK cell function in a great variety of gene knockout mice, providing a potential rationale for the mechanisms of the activation of NK cells in these animals. Moreover, we report on the recent advances in NK cell expansion and therapeutic delivery, and discuss the superiority of allogeneic supercharged NK cells over their autologous counterparts in the treatment of cancer patients. Furthermore, we discuss the potential loss of NK cell numbers and function at the neoplastic and preneoplastic stages of tumorigenesis as potential mechanisms for the induction and progression of pancreatic cancer. We also report on the novel ways of assessments of NK function within the 3D model of tumorospheres, to better represent the tumor microenvironment. Therefore, because of their indispensable role in targeting cancer stem-like/undifferentiated tumors, and a variety of other key functions of NK cells reviewed in this report, including their role in the selection and expansion of CD8 + T cells, and their potential functional inactivation by the tumors within the tumor microenvironment, which are mitigated by the mode of activation and expansion of NK cells, these cells should be placed high in the armamentarium of tumor immunotherapy. The combination of allogeneic supercharged NK cells with other therapeutic strategies such as the use of oncolytic viruses, ADCC-inducing antibodies, checkpoint inhibitors, CAR-T, CAR-NK, chemotherapeutic, and radiotherapeutic strategies can be used for the optimal treatment strategies.