Setting traps for NKG2A gives NK cell immunotherapy a fighting chance
Frank Cichocki, Jeffrey S. Miller
Frank Cichocki, Jeffrey S. Miller
Published April 15, 2019
Citation Information: J Clin Invest. 2019;129(5):1839-1841. https://doi.org/10.1172/JCI128480.
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Commentary

Setting traps for NKG2A gives NK cell immunotherapy a fighting chance

Abstract

The equilibrium of signaling through activating and inhibitory receptors dictates whether a given NK cell will execute cellular cytotoxicity. In this issue of the JCI, Kamiya et al. describe a novel approach to efficiently inhibiting surface expression of the inhibitory receptor CD94/NK group 2 member A (NKG2A) through retention of the protein in the endoplasmic reticulum. In adoptive transfer experiments into tumor-bearing immunodeficient mice, NKG2Anull NK cells were significantly more effective at eliminating HLA-E–expressing tumor cells than NKG2A+ NK cells. This study provides proof of concept for a new immunotherapeutic approach using NKG2Anull NK cells.

Authors

Frank Cichocki, Jeffrey S. Miller

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Figure 1

Trapping NKG2A in the ER enhances NK cell cytotoxicity against HLA-E–expressing tumors.

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Trapping NKG2A in the ER enhances NK cell cytotoxicity against HLA-E–exp...
(A) High HLA-E+ tumors deliver a potent inhibitory signal that leads to inhibition of NK cell function (five relative activating signal units vs. seven inhibitory). (B) Kamiya et al. developed a series of NKG2A PEBLs consisting of an scFv derived from an anti-NKG2A antibody linked to ER-retention domains. Transduction of human peripheral blood NK cells with retrovirus containing PEBL cassettes leads to efficient intracellular retention of NKG2A. (C) After NKG2A knockdown by PEBLs, the resulting NKG2Anull NK cells exhibit greater cytotoxicity against HLA-E–expressing tumor cells due to a net lack of inhibitory signaling (five relative activating signal units vs. one inhibitory).