The killing of neuroblastoma cells as a result of GD2-specific antibody-dependent cell-mediated cytotoxicity (ADCC) involves both licensed and unlicensed NK cells. Licensed NK cells have been exposed to self HLA class I molecules on autologous cells. These molecules bind to inhibitory killer cell immunoglobulin-like receptors (KIRs) on the NK cells and inhibit NK cell cytotoxicity towards self cells. Individuals lacking cognate HLA ligands for their inhibitory KIRs (a state referred to as 'missing KIR ligand') have unlicensed NK cells, which are hyporesponsive and include cells expressing inhibitory KIRs that bind non-self HLA class I molecules. The authors had previously noted that patients with KIR and HLA genotypes that indicate missing KIR ligand had a better prognosis after treatment with the GD2-specific monoclonal antibody 3F8 and autologous stem cell transplantation (ASCT). Why is this? Having established that this missing KIR ligand effect seems to be associated with the response to 3F8 and not to ASCT, the authors looked at the function of licensed and unlicensed NK cells in response to 3F8 treatment of neuroblastoma cells in vitro. Using blood samples containing either unlicensed or licensed NK cells, they found that both cell types were activated in response to 3F8 and a variety of neuroblastoma cell lines. However, the authors then asked whether neuroblastoma cells increase their expression of HLA class I molecules in response to treatment with 3F8. This was found to be the case, with both licensed and unlicensed NK cells initially responding, but as the neuroblastoma cells expressed HLA class I molecules the licensed NK cells were inhibited. Interferon-γ produced by the activated NK cells was shown to be responsible for the induction of HLA class I expression by the neuroblastoma cells.
These results indicate that, of the NK cells in patients with missing KIR ligand, the unlicensed NK cells (particularly those with KIRs that bind to non-self HLA ligands) are crucial mediators of ADCC. Therefore, KIR and HLA genotypes might be useful prognostic markers for the treatment of patients with high-risk neuroblastoma using monoclonal antibodies.
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