NK cell killing of AML and ALL blasts by Killer-Immunoglobulin Receptor (KIR) negative NK cells after NKG2A and LIR-1 blockade

• Published in: Biology of blood and marrow transplantation 2010-02, Vol.16 (5), p.612-621
• Main Authors: Godal, Robert, Bachanova, Veronika, Gleason, Michelle, McCullar, Valarie, Yun, Gong H., Cooley, Sarah, Verneris, Michael R., McGlave, Philip B., Miller, Jeffrey S.
• Format: Article
• Language: English
• ISSN: 1083-8791; 1523-6536
• DOI: 10.1016/j.bbmt.2010.01.019

Although NK cell alloreactivity has been dominated by studies of KIR, we hypothesized that NKG2A and LIR-1, present on 53±13% and 36±18% of normal NK cells, plays a role in NK cell killing of primary leukemia targets. KIR − cells, which comprise nearly half of the circulating NK cell population, exhibited tolerance to primary leukemia targets, suggesting signaling through other inhibitory receptors. Both AML and ALL targets could be rendered susceptible to lysis by fresh resting KIR − NK cells when inhibitory receptor-MHC class I interactions were blocked by pan-HLA antibodies demonstrating that these cells were functionally competent. Blockade of a single inhibitory receptor resulted in slight increases in killing, while combined LIR-1 and NKG2A blockade consistently resulted in increased NK cell cytotoxicity. Dual blockade of NKG2A and LIR-1 led to significant killing of targets by resting KIR − NK cells showing that this population is not hyporesponsive. Together these results suggest that alloreactivity of a significant fraction of KIR − NK cells is determined by NKG2A and LIR-1. Thus strategies to interrupt NKG2A and LIR-1 in combination with anti-KIR blockade hold promise for exploiting NK cell therapy in acute leukemia.