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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 Article has an altmetric score of 9

Unlicensed NK cells target neuroblastoma following anti-GD2 antibody treatment

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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 3

Licensed NK cells are selectively inhibited by HLA class I ligands induced on NB targets.

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Licensed NK cells are selectively inhibited by HLA class I ligands induc...
(A) Incubation with IFN-γ results in increased HLA class I antigen expression on LAN-1 and BE(2)N cells. HLA-Bw4 and HLA-E antigens are readily induced on BE(2)N but not LAN-1 cells. (B) CD107 degranulation and IFN-γ production in NKG2A-negative, KIR-positive NK cells in response to IFN-γ–treated NB targets in the presence of 3F8. When NK cells from individual no. 17 (HLA-C1/C1/Bw6/Bw6) are incubated with LAN-1 cells, mimicking effectors and NB cells in a patient lacking HLA-C2 and HLA-Bw4 ligands, both NS-KIR–positive (KIR2DL1 single positive [KIR2DL1sp] and KIR3DL1sp) and S-KIR–positive (KIR2DL3sp) NK cells are activated in the presence of 3F8, but only KIR2DL3 spNK cells are inhibited by IFN-γ–induced expression of self HLA on tumor target. When NK cells from individual no. 20 (HLA-C1/C2/Bw4/Bw4) are incubated with BE(2)N cells, mimicking effectors and NB cells in a patient with all ligands present, S-KIR–positive NK subsets (KIR2DL1sp, KIR2DL3sp, and KIR3DL1sp) are inhibited by IFN-γ–induced expression of cognate ligands on the tumor target. In both individuals, blocking antibodies to HLA class I fully restores response among S-KIR–positive NK cells. (C) Aggregate CD107 response among NK populations from 9 HLA-C1/C1 individuals to LAN-1 cells. HLA class I upregulation on the target inhibits S-KIR spNK cells, resulting in a comparatively stronger response from NS-KIR spNK cells (P = 0.003). Aggregate CD107 response among spNK cells from 3 HLA-C1/C2/Bw4 individuals to BE(2)N demonstrates that HLA class I upregulation on the target inhibits all self-specific NK subsets. Symbols represent individual samples (mean ± SEM). **P < 0.01,***P < 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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