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.
Highlights
Neuroblastoma (NB), an embryonal malignancy of neuroectodermal origin, is the most common extracranial solid tumor of childhood
We previously reported that killer cell immunog lobulin-like receptors (KIRs) ligand implies that unlicensed NK cells expressing NS-KIRs in patients receiving autologous stem cell transplantation (ASCT) with 3F8 had superior overall survival (OS) and progres- these individuals become activated and contribute significantly to sion-free survival (PFS) if they lacked HLA class I ligands for tumor control
In vitro, licensed NK cells expressing S-KIRs and unlicensed NK cells expressing NS-KIRs are both activated by NB targets in the presence of 3F8, but only the licensed cells are inhibited by cytokine-induced expression of self-HLA molecules on tumor targets
Summary
Neuroblastoma (NB), an embryonal malignancy of neuroectodermal origin, is the most common extracranial solid tumor of childhood. Treatment of patients with high-risk NB with monoclonal antibodies (mAb) targeting the disialoganglioside surface antigen GD2 has resulted in lower recurrence rates and improved overall survival (OS) [3,4,5]. NK activity is regulated by inhibitory and activating signals following engagement of cell membrane receptors with their cognate ligands on target cells [6]. Untreated NB tumors and cell lines are widely reported to have reduced to no HLA class I expression, rendering them potentially susceptible to NK killing due to lack of engagement of HLA class I–specific inhibitory killer cell immunog lobulin-like receptors (KIRs) [7, 8]. To evade NK surveillance, NB cells exhibit poor cell surface expression of the activating ligands MICA, MICB, and ULBPs; and high serum concentrations of soluble MICA in patients with NB results in depressed
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
