Natural killer cells

Natural killer (NK) cells display potent cytolytic activity and broad effector functions due to their rapid production of cytokines. CD16a is the sole IgG Fc receptor (FcγRIIIa) expressed by human NK cells and it binds to IgG1 and IgG3 antibodies attached to target cells to facilitate antibody-dependent cell-mediated cytotoxicity (ADCC). A number of therapeutic antibodies have been generated against a variety of antigens expressed by cancer cells, and several clinically successful antibodies utilize ADCC as a mechanism of action. Surface levels of CD16a, however, are rapidly downregulated by ADAM17 upon NK cell activation. CD16a downregulation by NK cells has also been shown to occur in the tumor environment of patients, in individuals receiving therapeutic antibodies, and upon their ex vivo expansion for adoptive transfer, and this process appears to be immune suppressive. Our lab is examining ADAM17 as a checkpoint target to prevent CD16a downregulation and improve NK cell function in the tumor environment. In addition, our team is engineering enhanced versions of CD16a to express in NK cells derived from patients and from induced pluripotent stem cells to be used for adoptive cell therapy.