Natural killer (NK) cells are innate immune lymphocytes that express CD56 and lack CD3 surface antigens. NK cells do not require the presence of specific tumor antigen for the recognition and killing of cancer cells. NK cell recognition of tumor targets is regulated through a balance of activating and inhibitory signals. NK cells also have the ability to directly kill target cells through antibody-dependent cell cytotoxicity (ADCC) via the membrane Fc-γ receptor III (CD16) which binds to IgG antibodies and can also indirectly induce tumor apoptosis through cytokine secretion, directly through the perforin-granzyme pathway, or through death-receptor ligands such as TRAIL or Fas ligand expressed on their cell surfaces.
Tumors with low HLA class I expression are more susceptible to NK cell cytotoxicity. Adoptive infusion of allogeneic NK cells in patients who lack MHC class I molecules for one or more KIRs present in the donor may overcome NK cell-mediated KIR inactivation. Agents that increase surface expression of cellular death-receptors which render tumors more susceptible to NK cell cytotoxicity include bortezomib and depsipeptide. In vitro expanded autologous NK cells isolated from patients with cancers have been shown to exhibit significantly more cytotoxicity when tumors were pretreated with bortezomib compared with untreated tumor controls. Combining adoptive NK cell transfer with monoclonal antibody therapy could augment NK cell-mediated ADCC.
KeywordsAntibody-dependent cell cytotoxicity (ADCC) Chimeric antigen receptors (CAR) Interleukin-2 (IL-2) Killer immunoglobulin-like receptors (KIRs) Natural killer (NK) cells ADCC CAR Clinical trials Effector assessment IL-2 activation In cancer In vitro and in vivo susceptibility KIR-mediated inactivation of Tumor susceptibility
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