OR11 Low content of activating killer immunoglobulin-like receptors predispose to hematological malignancies

Abstract

Aim Natural killer (NK) cells are critical in surveillance against viral infections and malignancies. Central to the regulation of NK cells is incredible diversity of activating and inhibitory Killer cell Ig-like receptors (KIR) that manifests in differential NK cell responses among different individuals. This diversity together with variability in KIR-HLA class I ligand is expected to modify the susceptibility to hematological malignancies. Here, we addressed this effect by studying comprehensive KIR gene profile in a Canadian cohort of myelogenous and lymphocytic leukemias. Methods A retrospective cohort of 837 subjects including patients of hematological malignancies (n = 377; myelogenous leukemias, n = 215; lymphocytic leukemia, n = 152) and healthy individuals (n = 460) were recruited. The KIR gene profiles were obtained using next generation sequencing and HLA class I genotypes were obtained by Luminex-based rSSO. Different case-control cohorts were tested for KIR and HLA-class I distribution (gene content, haplotypes and KIR-ligand combinations) by univariate and multivariate analysis. Results Lower content of activating KIR genes strongly correlated with increased incidences of hematological malignancies in a dose-dependent manner. The activating KIR content of ⩾3 activating KIR (=0.018, OR = 0.72, 95% CI = 0.55—0.95), ⩾4 activaing KIRs ( P = 0.004, OR = 0.66, 95% CI = 0.50-0.87) and ⩾5 activating KIRs ( P = 0.001, OR = 0.58, 95% CI = 0.42-0.81) were observed significantly more frequent in healthy controls as compared to patients of Hematological Malignancies. The strongest association was observed with lymphocytic leukemia while a trend of similar but non-significant association was observed with myelogenous leukemia. Conclusions Patients of hematological malignancies in general and that of lymphocytic leukemia in particular have low content of activating KIR genes. The findings suggest that low activating KIR gene content could lead to a deficient NK cell mediated immune surveillance of cancer cells.