Unlicensed NK cells target neuroblastoma following anti-GD2 antibody treatment
Nidale Tarek, … , Nai-Kong V. Cheung, Katharine C. Hsu
Nidale Tarek, … , Nai-Kong V. Cheung, Katharine C. Hsu
Published August 6, 2012
Citation Information: J Clin Invest. 2012;122(9):3260-3270. https://doi.org/10.1172/JCI62749.
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Research Article

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.

Authors

Nidale Tarek, Jean-Benoit Le Luduec, Meighan M. Gallagher, Junting Zheng, Jeffrey M. Venstrom, Elizabeth Chamberlain, Shakeel Modak, Glenn Heller, Bo Dupont, Nai-Kong V. Cheung, Katharine C. Hsu

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Figure 4

IFN-γ released by activated NK cells induces upregulation of HLA class I on NB cells in vitro.

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IFN-γ released by activated NK cells induces upregulation of HLA class I...
(A) HLA-Bw4 and HLA-A, HLA-B, and HLA-C expression on the LAN-1 and BE(2)N NB cell lines is shown following 72 hours in different culture conditions. Supernatants collected from PBMCs coincubated with LAN-1 and BE(2)N cells and 3F8, with or without GM-CSF, induced HLA class I expression on LAN-1 and BE(2)N cells, respectively; in comparison, supernatant collected from PBMCs incubated with or without GM-CSF did not induce HLA expression. (B) By ELISA, PBMCs alone or PBMCs with GM-CSF produced no or minimal IFN-γ. PBMCs activated by LAN-1 cells in the presence of 3F8 and GM-CSF released a substantial amount of IFN-γ compared with baseline and reached 60 pg/ml at 24 hours. (C) Titration assays demonstrate that HLA class I expression can be induced on LAN-1 and BE(2)N cells with 10 pg/ml IFN-γ and that expression increased in a dose-dependent manner.