Fig. 3

Harnessing NK cells for cancer immunotherapy. Several approaches are currently being actively pursued to exploit NK cells for cancer immunotherapy. A CAR NK cells. In CAR NK cells, artificial cell surface receptor on NK cells specifically recognizes tumor antigens on target/cancer cells and CAR NK cells destroy those cells. CAR can use the same CAR construct as used in CAR T cells with CD3ζ intracellular domain, or NK-specific activating domains, such as 2B4, DAP10 and DAP12. B Blockage of negative regulators on NK cells. The activity of NK cells is tightly regulated by both activating and inhibiting signaling pathways. The human killer cell immunoglobulin-like receptors (KIR; also known as CD158) are key negative regulators of NK cells. Engagement of KIR by MHC-I molecules on normal nucleated cells inhibits NK cell activity and induces “self” tolerance. Blockage of KIR activates NK cells to kill target cells. C Antibody-dependent cell-mediated cytotoxicity (ADCC). Antibody binds to its cognate antigen on target/cancer cells. Then the Fc region of the antibody is recognized by the Fc receptor, CD16, on NK cells which subsequently kills target/cancer cells coated with antibody. D Bi- and tri-specific killer engagers (BiKEs and TriKEs). Similar to ADCC, BiKEs and TriKEs bridge NK cells to target/cancer cells for cell killing. While the Fc portion of an antibody binds to the Fc receptor to mediate cell killing at ADCC, BiKEs and TriKEs contain a single variable portion (VH and VL) of antibody to engage the Fc receptor (CD16) on NK cells and another (for BiKE) or two other (for TriKE) variable portions of antibodies to bind to the antigen(s) on target/cancer cells. This figure was created at BioRender.com