Natural killer cell receptors: alterations and therapeutic targeting in malignancies

Numerous newly identified activating and inhibitory NK cell receptors and their engagement by cognate ligands on target tumor cells regulate NK cell antitumor activity. Alterations in NK cell receptor expression and signaling underlie diminished cytotoxic NK cell function. Cytokines, IFN-alpha, IL-2, IL-12, IL-15 and IL-18, applied systemically and for ex vivo activation and expansion of NK cells have improved NK cell antitumor activity by increasing the expression of NK cell activating receptors and by inducing cytotoxic effector molecules. Moreover, it has been recognized that classical and novel pharmacological agents upregulate cognate ligands for activating receptors on tumor cells and provide better NK cell antitumor response. Some other immunotherapeutic approaches in cancer in the setting of donor-recipient KIR/HLA mismatch have evolved with the aim to potentiate NK cell activity in allogeneic hematopoietic stem cell transplantation that lead to beneficial graft vs. tumor effect. Therefore, better understanding of NK cell activating and inhibitory receptor biology is needed to assist in developing novel approaches to effectively manipulate NK cells and create effective NK cell-based immunotherapy for treatment of cancer patients.