Natural killer cells; diverse functions in tumor immunity and defects in pre-neoplastic and neoplastic stages of tumorigenesis

Abstract Natural killer (NK) cells are the key immune effectors with the ability to mediate selection and differentiation of a number of different cancer stem cells/undifferentiated tumors via lysis, and secreted or membrane bound IFN-γ and TNF-α respectively, leading to curtailment of tumor growth and metastasis. In this review, we present an overview of our recent findings on the biology and significance of NK cells in selection/differentiation of stem-like tumors using in vitro and in vivo studies conducted in the humanized-BLT mice and those of cancer patients. In addition, we present current advances in NK cell expansion and therapeutic delivery, and discuss the utility of allogeneic super-charged NK cells in the treatment of cancer patients. Moreover, we discuss the potential loss of NK cell numbers and function at the neoplastic and pre-neoplastic stages of tumorigenesis in potential induction and progression of pancreatic tumors. Therefore, because of their indispensable role in targeting cancer stem-like/undifferentiated tumors, NK cells should be placed high in the armamentarium of tumor immunotherapy. Combination of allogeneic super-charged NK cells with other immunotherapeutic strategies such as oncolytic viruses, ADCC inducing antibodies, check point inhibitors, CAR-T, CAR-NK, and chemotherapeutic and radiotherapeutic strategies can be used for the ultimate goal of tumor eradication.