KIR2DS2 expression identifies NK cells with enhanced anti-cancer activity

Natural killer (NK) cells are promising cellular therapeutics against haematological and solid malignancies. Immunogenetic studies have identified that various activating killer cell immunoglobulin-like receptors (KIR) are associated with cancer outcomes. Specifically, KIR2DS2 has been associated with reduced incidence of relapse following transplantation in haematological malignancies and improved outcomes in solid tumours, but the mechanism remains obscure. Therefore we investigated how KIR2DS2 expression impacts NK cell function. Using a novel flow cytometry panel, we show that human NK cells with high KIR2DS2 expression have enhanced spontaneous activation against malignant B cell lines, liver cancer cell lines and primary chronic lymphocytic leukaemia (CLL) cells. Surface expression of CD16 was increased on KIR2DS2 high NK cells and accordingly, KIR2DS2 high NK cells had increased activation against lymphoma cells coated with the clinically relevant anti-CD20 antibodies rituximab and obinutuzumab. Bulk RNA sequencing revealed that KIR2DS2 high NK cells have upregulation of NK mediated cytotoxicity, translation and FCGR gene pathways. We developed a novel single-cell RNA sequencing technique to identify KIR2DS2+ NK cells and this confirmed that KIR2DS2 is associated with enhanced NK cell mediated cytotoxicity. This study provides evidence that KIR2DS2 marks a population of NK cells primed for anti-cancer activity and indicates that KIR2DS2 is an attractive target for NK based therapeutic strategies.