Figure 4.

Therapeutic targeting of the NKG2D-MICA/B pathway. (a) The activating NKG2D receptor is expressed by human NK cells, CD8 T cells, NKT cells, and γδ T cells. It binds to the stress-induced ligands MICA and MICB (MICA/B) on tumor cells, but tumors evade an NKG2D-mediated immune attack by proteolytic shedding of MICA/B through the coordinated action of the ERp5 disulfide isomerase and the proteases ADAM10 and ADAM17. A monoclonal antibody against the MICA/B α₃ domain inhibits proteolytic shedding and induces an NK cell–mediated immune attack against metastases. (b) A vaccine targeting the MICA/B α₃ domain induces a T cell response against this stress protein as well as polyclonal antibodies that inhibit MICA/B shedding. This vaccine retains activity against MHC-I-deficient tumor cells based on the coordinated action of CD4 T cells and NK cells. CD4 T cells recruit NK cells into tumors, while NK cells kill tumor cells following activation through the NKG2D and CD16 receptors. Abbreviations: DC, dendritic cell; KIR, killer cell immunoglobulin-like receptor; mAb, monoclonal antibody; TCR, T cell receptor.