Figure 2.

Possible NKG2D-MICA/B-based immunotherapy approaches. Different strategies can be used to induce NK cell activation to improve HCC killing. (A) MICA/B α3 domain–specific mAb is able to induce NK cell-mediated antibody-dependent cytotoxicity (ADCC). (B) Bi-specific or tri-specific killer engagers (BiKE or TriKE), capable of binding NKG2D expressed on NK cells and one tumor antigen on HCC can maximize targeting of tumor cells. (C) A chimeric antigen receptor containing the NKG2D extracellular domain that binds to MICA/B ligands, fused to a spacer and trans-membrane domain. The intracellular domain contains costimulatory domains, such as CD28 and 4-1BB and the CD3ζ chain, which drive signal activation and amplification of CAR-NK cells. (D) cytokines, such as interleukin (IL)-15, can also be employed to generate cytokine induced NK cells.