KIR3DL1 allelic polymorphism and HLA-B epitopes modulate response to anti-GD2 monoclonal antibody in patients with neuroblastoma Journal Article

Authors: Forlenza, C. J.; Boudreau, J. E.; Zheng, J.; Le Luduec, J. B.; Chamberlain, E.; Heller, G.; Cheung, N. K. V.; Hsu, K. C.
Article Title: KIR3DL1 allelic polymorphism and HLA-B epitopes modulate response to anti-GD2 monoclonal antibody in patients with neuroblastoma
Abstract: 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 immunoglobulinlike 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(2)], 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(2) 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. © 2016 by American Society of Clinical Oncology.
Journal Title: Journal of Clinical Oncology
Volume: 34
Issue: 21
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2016-07-20
Start Page: 2443
End Page: 2451
Language: English
DOI: 10.1200/jco.2015.64.9558
PROVIDER: scopus
PUBMED: 27069083
PMCID: PMC4962735
Notes: Article -- Export Date: 2 August 2016 -- Source: Scopus
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MSK Authors
  1. Junting Zheng
    128 Zheng
  2. Glenn Heller
    284 Heller
  3. Nai-Kong Cheung
    430 Cheung
  4. Katharine C Hsu
    131 Hsu