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 2

3F8 activates NK cells expressing S-KIRs, NS-KIRs, and NKG2A against NB targets.

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3F8 activates NK cells expressing S-KIRs, NS-KIRs, and NKG2A against NB ...
In healthy individuals, CD107 degranulation was analyzed in the presence of NB target cells (LAN-1 cells), with and without mAb, among subsets of NK cells. (A) In individual no. 8, S-KIR spNK cells demonstrate strong activation in response to K562 compared with that of NS-KIR spNK cells. All NK populations show minimal activation in response to LAN-1 cells alone but are activated by the addition of 3F8 in response to LAN-1 cells. Data represent the average of 3 separate experiments. (B) Aggregate function of S-KIR and NS-KIR spNK cells from 16 healthy individuals. Addition of 3F8 to LAN-1 cells results in activation of S-KIR–positive, NS-KIR–positive, and KIR-negative NK cells (P < 0.0001), with S-KIR spNK cells more responsive (P = 0.004) and KIR-negative NK cells less responsive (P = 0.006) than NS-KIR spNK cells. (C) NKG2A expression contributes to NK response to LAN-1 cells in the presence of 3F8 among NK cells expressing S-KIR, and NS-KIR (P < 0.0001), and KIR-negative NK cells (P = 0.0004). NS-KIR–positive, NKG2A-negative NK cells are more responsive than KIR-negative, NKG2A-negative NK cells (P = 0.0008) and are equally responsive to KIR-negative, NKG2A-positive cells (P = 0.13). Symbols represent individual samples (mean ± SEM). *P < 0.05, **P < 0.01, ***P < 0.001.