KIR3DL1 Allelic Polymorphism and HLA-B Epitopes Modulate Response to Anti-GD2 Monoclonal Antibody in Patients With Neuroblastoma

J Clin Oncol. 2016 Jul 20;34(21):2443-51. doi: 10.1200/JCO.2015.64.9558. Epub 2016 Apr 11.


Purpose: In patients with neuroblastoma (NB), treatment with anti-GD2 monoclonal antibody (mAb) directs natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) against tumor cells. However, tumor cytotoxicity is attenuated by ligation of inhibitory killer immunoglobulin-like receptors (KIRs) by HLA class I molecules. KIR3DL1 polymorphism influences its ability to engage HLA-Bw4 ligands. We tested the hypothesis that poorly interacting combinations of KIR3DL1 and HLA ligands are more permissive of mAb-mediated antitumor effect.

Methods: KIR3DL1 and HLA-B subtyping were performed with a multiplex intermediate-resolution polymerase chain reaction assay for a cohort of 245 patients who were treated with antibody 3F8 for high-risk NB. Patient outcomes were analyzed according to expected degree of interaction between KIR3DL1 and HLA-B subtypes and grouped as strong, weak, or noninteractors. A comparison of NK response to 3F8 mAb opsonized NB cells between strong- and noninteracting donors was performed by flow cytometry.

Results: KIR3DL1 and HLA-B subtype combinations associated with noninteraction as a result of lack of receptor expression [KIR3DL1(-)], failure of interaction with inhibitory ligands [KIR3DS1(+)], or absence of KIR ligands resulted in significantly improved overall and progression-free survival. Patients with KIR3DL1 and HLA-B subtype combinations that were predictive of weak interaction had superior outcomes compared with those that were predictive of strong interaction; however, both groups were inferior to those with noninteracting subtype combinations. In vitro analysis of 3F8-mediated ADCC showed that KIR3DL1(-) and 3DS1(+) NK cells were insensitive to inhibition by HLA-Bw4-expressing NB targets.

Conclusion: We conclude that KIR3LD1 and HLA-B allele combinations can have a prognostic impact on patient survival after treatment with anti-GD2 mAb that relies on NK-ADCC. The survival advantage seen in noninteracting combinations supports the therapeutic disinhibition of individuals with strongly interacting KIR and ligand pairs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Alleles
  • Antibodies, Monoclonal / therapeutic use*
  • Child
  • Child, Preschool
  • Epitopes
  • Gangliosides / immunology*
  • HLA-B Antigens / immunology*
  • Humans
  • Killer Cells, Natural / immunology
  • Neuroblastoma / drug therapy*
  • Neuroblastoma / genetics
  • Neuroblastoma / immunology
  • Neuroblastoma / mortality
  • Polymorphism, Genetic*
  • Receptors, KIR3DL1 / genetics*
  • Retrospective Studies


  • Antibodies, Monoclonal
  • Epitopes
  • Gangliosides
  • HLA-B Antigens
  • KIR3DL1 protein, human
  • Receptors, KIR3DL1
  • ganglioside, GD2