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.

Figure 1. Trapping NKG2A in the ER enhances NK cell cytotoxicity against HLA-E–expressing tumors.

(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 NKG2A^null 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).