Unlicensed NK cells target neuroblastoma following anti-GD2 antibody treatment Journal Article


Authors: Tarek, N.; Luduec, J. B. L.; Gallagher, M. M.; Zheng, J.; Venstrom, J. M.; Chamberlain, E.; Modak, S.; Heller, G.; Dupont, B.; Cheung, N. K. V.; Hsu, K. C.
Article Title: Unlicensed NK cells target neuroblastoma following anti-GD2 antibody treatment
Abstract: 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.
Keywords: child; preschool child; disease-free survival; survival rate; unclassified drug; human cell; major clinical study; antineoplastic agents; antigen expression; cells, cultured; cancer immunotherapy; granulocyte macrophage colony stimulating factor; in vitro study; cell line, tumor; monoclonal antibody; lymphocyte activation; antibodies, monoclonal; leukocytes, mononuclear; immunoglobulin g; infant; neuroblastoma; hla antigen class 1; histocompatibility antigens class i; natural killer cell; killer cells, natural; receptors, kir; interferon-gamma; isotretinoin; cancer control; beta glucan; cell activity; antibody dependent cellular cytotoxicity; coculture techniques; gangliosides; kaplan-meier estimate; gd2 monoclonal antibody; antibody-dependent cell cytotoxicity
Journal Title: Journal of Clinical Investigation
Volume: 122
Issue: 9
ISSN: 0021-9738
Publisher: American Society for Clinical Investigation  
Date Published: 2012-09-04
Start Page: 3260
End Page: 3270
Language: English
DOI: 10.1172/jci62749
PROVIDER: scopus
PMCID: PMC3428088
PUBMED: 22863621
DOI/URL:
Notes: --- - "Cited By (since 1996): 1" - "Export Date: 1 October 2012" - "CODEN: JCINA" - "Source: Scopus"
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Citation Impact
MSK Authors
  1. Junting Zheng
    149 Zheng
  2. Glenn Heller
    351 Heller
  3. Nai-Kong Cheung
    530 Cheung
  4. Shakeel Modak
    185 Modak
  5. Nidale Tarek
    6 Tarek
  6. Katharine C Hsu
    148 Hsu
  7. Bo Dupont
    196 Dupont