Fig. 1.

Representative examples of combinatorial approaches of natural killer (NK) cell immunotherapy with chemotherapy, radiation, or monoclonal antibody (mAb) therapy. One approach (A) would be to combine NK cell immunotherapy with chemotherapy (e.g., bortezomib), which downregulates cell surface expression of human leukocyte antigen (HLA) class I on target cells (missing self) and enhances NK cell-mediated lysis of tumor targets. Another approach (B) is to combine NK cell therapy with radiation therapy, which is known to increase the expression of NK activating ligands (e.g., NKG2D ligands MICA and MICB) on malignant cells (induced self), thus rendering tumors more susceptible to NK cell cytotoxic activity. The third approach (C) is to combine NK cell immunotherapy with mAb therapy (e.g., the anti-HER2/neu mAb trastuzumab). NK cells express an activating Fc receptor (FcγRIIIa, CD16) that recognizes the constant region of IgG and allows them to kill antibody-coated target cells via antibody-dependentcell-mediated cytotoxicity.