Diversity of molecular interactions between NK cells and acute leukemic cells: KIR2DL5 drastically limits NK cell responses against leukemic cells

NK cells naturally recognize and eliminate leukemic cells. However, the molecular interactions that govern these responses are diverse due to the large number of activating and inhibitory NK receptors that modulate NK functions and the diversity of corresponding ligands that are differentially expressed in acute lymphoblastic and myeloid leukemias. We identified resting NKG2A+ NK cells and NKG2A+KIR+ NK cell subsets that are most effective in eliminating lymphoid and myeloid leukemic cells respectively. The NKG2A+KIR+/-CD57- subsets show high expression of activating receptors and a functional transcriptomic profile, but differ in KIR2DL5 expression. The frequency of KIR2DL5+ NK cells increases with the number of expressed KIR. Furthermore, KIR2DL5 is preferentially co-expressed with KIR2DL1 and is negatively regulated by NKG2A. Of note, CD57 expression, regardless of the subset considered, is associated with reduced receptor expression, consistent with its reduced cytotoxic potential. Furthermore, we have shown that molecular interactions between NK cells and leukemic cells influence NK cell responses, particularly the inhibitory KIR2DL5-PVR axis. The integration of these data is of importance for the optimization of NK cell-based immunotherapies, as the selection of NK cell donors represents a key parameter for the improvement of these therapies. In this study, we aim to identify NK subsets with the highest efficacy against acute leukemia by considering the NK cell phenotype in the context of KIR and HLA genotypes, age, sex, and CMV status. To complement the phenotypic study, we analyzed the transcriptional profiles of the three cell subsets NKneg, NKALL and NKAML. RNA-seq was then applied to the different samples in order to establish the transcriptomic signature associated with these different NK cell subsets.