Unlicensed NK cells target neuroblastoma following anti-GD2 antibody treatment

• Published in: The Journal of clinical investigation 2012-09, Vol.122 (9), p.3260-3270
• Main Authors: Tarek, Nidale, Le Luduec, Jean-Benoit, Gallagher, Meighan M, Zheng, Junting, Venstrom, Jeffrey M, Chamberlain, Elizabeth, Modak, Shakeel, Heller, Glenn, Dupont, Bo, Cheung, Nai-Kong V, Hsu, Katharine C
• Format: Article
• Language: English
• Subjects: Antibodies; Antibodies, Monoclonal - pharmacology; Antibody-Dependent Cell Cytotoxicity; Antineoplastic Agents - pharmacology; Biomedical research; Cell Line, Tumor - drug effects; Cells, Cultured; Chemotherapy; Coculture Techniques; Cytotoxicity; Disease-Free Survival; Gangliosides - immunology; Histocompatibility Antigens Class I - metabolism; Humans; Immunoglobulin G - pharmacology; Immunoglobulins; Infant; Interferon-gamma - metabolism; Interferon-gamma - physiology; Kaplan-Meier Estimate; Killer Cells, Natural - drug effects; Killer Cells, Natural - metabolism; Killer Cells, Natural - physiology; Leukocytes, Mononuclear - metabolism; Licenses; Ligands; Lymphocyte Activation - drug effects; Neuroblastoma; Neuroblastoma - drug therapy; Neuroblastoma - immunology; Neuroblastoma - mortality; Patients; Receptors, KIR - metabolism; Tumors
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI62749

Survival outcomes for patients with high-risk neuroblastoma (NB) have significantly improved with anti-disialoganglioside GD2 mAb therapy, which promotes NK cell activation through antibody-dependent cell-mediated cytotoxicity. NK cell activation requires an interaction between inhibitory killer cell immunoglobulin-like receptors (KIRs) and HLA class I ligands. NK cells lacking KIRs that are specific for self HLA are therefore "unlicensed" and hyporesponsive. mAb-treated NB patients lacking HLA class I ligands for their inhibitory KIRs have significantly higher survival rates, suggesting that NK cells expressing KIRs for non-self HLA are mediating tumor control in these individuals. We found that, in the presence of mAb, both licensed and unlicensed NK cells are highly activated in vitro. However, HLA class I expression on NB cell lines selectively inhibited licensed NK cell activity, permitting primarily unlicensed NK cells to mediate antibody-dependent cell-mediated cytotoxicity. These results indicate that unlicensed NK cells play a key antitumor role in patients undergoing mAb therapy via antibody-dependent cell-mediated cytotoxicity, thus explaining the potent "missing KIR ligand" benefit in patients with NB.