Expression of NK Cell Receptor Ligands on Leukemic Cells Is Associated with the Outcome of Childhood Acute Leukemia.

Abstract

Simple SummaryNatural killer cells (NK cells) of the innate immune system are suspected of playing an important role in eliminating residual leukemia cells during maintenance chemotherapy given to children with acute lymphoblastic leukemia for about two years. This study analyzes the expression of ligands for the receptors that regulate the function of NK cells on leukemic cells of more than one hundred children with acute lymphoid and myeloid leukemia. Our results show that the loss of expression of some molecules involved in the activation of NK cells is associated with poorer survival. In addition, a genetic combination of molecules that interact to regulate NK cell function seems to be associated with a higher relapse rate during/after chemotherapy and shorter patient survival. Children who carry this genetic combination are refractory to current chemotherapy treatments, and stem cell transplantation does not seem to contribute to their cure either, and therefore, they should be considered as candidates for alternative biological therapies that might offer better results.Acute leukemia is the most common malignancy in children. Most patients are cured, but refractory/relapsed AML and ALL are the first cause of death from malignancy in children. Maintenance chemotherapy in ALL has improved survival by inducing leukemic cell apoptosis, but immune surveillance effectors such as NK cells might also contribute. The outcome of B-ALL (n = 70), T-ALL (n = 16), and AML (n = 16) pediatric patients was evaluated according to leukemic cell expression of ligands for activating and inhibiting receptors that regulate NK cell functioning. Increased expression of ULBP-1, a ligand for NKG2D, but not that of CD112 or CD155, ligands for DNAM-1, was associated with poorer 5-year event-free survival (5y-EFS, 77.6% vs. 94.9%, p < 0.03). Reduced expression of HLA-C on leukemic cells in patients with the KIR2DL1/HLA-C*04 interaction was associated with a higher rate of relapse (17.6% vs. 4.4%, p = 0.035) and lower 5y-EFS (70.6% vs. 92.6%, p < 0.002). KIR2DL1/HLA-C*04 interaction was an independent predictive factor of events (HR = 4.795, p < 0.005) or death (HR = 6.731, p < 0.005) and might provide additional information to the current risk stratification. Children who carry the KIR2DL1/HLA-C*04 interaction were refractory to current chemotherapy treatments, including allogeneic stem cell transplantation; therefore, they should be considered as candidates for alternative biological therapies that might offer better results.