Multiple Defects of Natural Killer Cells in Cancer Patients: Anarchy, Dysregulated Systemic Immunity, and Immunosuppression in Metastatic Cancer

We have previously demonstrated that natural killer (NK) cells are the main immune effectors that can mediate selection and differentiation of different cancer stem cells and undifferentiated tumors via lysis and secreted or membrane-bound interferon-γ and tumor necrosis factor-α, respectively. This leads to growth inhibition and tumor metastasis curtailment. In this review, we present an overview of our findings on NK cell biology and its significance in selection and differentiation of stem-like tumors using in vitro and in vivo studies conducted in nonobese diabetic/severe combined immunodeficiency (scid)/interleukin-Rγ--, humanized-bone-marrow/liver/thymus (hu-BLT) mice, and those of human cancer patients. Moreover, we present recent advances in NK cell expansion and therapeutic delivery and discuss the superiority of allogeneic supercharged NK cells over their autologous counterparts for cancer treatment. We review potential loss of NK cell numbers and function at neoplastic and preneoplastic stages of tumorigenesis as a potential mechanism for pancreatic cancer induction and progression. We believe that NK cells should be placed highly in the armamentarium of tumor immunotherapy due to their indispensable role in targeting cancer stem-like/poorly differentiated tumors and a variety of other key NK cell functions that are discussed in this report, including their role in CD8+ T-cell expansion and targeting gene knockout or dedifferentiated tumors. The combination of allogeneic supercharged NK cells and other immunotherapeutic strategies such as oncolytic viruses, antibody-dependent cellular cytotoxicity-inducing antibodies, checkpoint inhibitors, chimeric antigen receptor (CAR)-T cells and CAR-NK cells, chemotherapeutics, and radiotherapeutic strategies can be used for optimal eradication of tumors.