Mechanisms of leukemia-induced immunosuppression

Abstract: This thesis aimed to define the role of reactive oxygen species (ROS), produced by the NADPH oxidase of myeloid cells, in the regulation of lymphocyte function with focus on ROS-induced dysfunction of natural killer (NK) cells and T lymphocytes in myeloid leukemia. In Paper I, a novel mechanism is presented by which specifically activated T lymphocytes evade inactivation by ROS after antigen presentation. Antigen-presenting dendritic cells were found to induce ROS-neutralizing thiols on the surface of antigen-specific T cells, but not on T cells that lacked antigen specificity. These findings may explain why antigen-specific T cells remain viable under conditions of oxidative stress. Paper II shows that subsets of leukemic cells recovered from patients with acute myeloid leukemia (AML) produce and release ROS via a membrane-bound NADPH oxidase, and that ROS-producing leukemic cells initiate a PARP-1-dependent pathway of cell death (parthanatos) in NK cells and T cells. The results presented in Paper III demonstrate that treatment of AML patients with a NADPH oxidase inhibitor (histamine dihydrochloride) was preferentially efficacious among patients with monocytic leukemias (FAB classes M4 and M5), in which cells of the leukemic clone expressed a ROS-producing NADPH oxidase and functional histamine H2 receptors. The results presented in Paper IV imply that malignant cells recovered from patients with chronic myeloid leukemia utilize the ROS/PARP-1 axis to induce NK cell parthanatos and that PARP-1 inhibition maintains functions of T cells and NK cells under conditions of oxidative stress. Paper V aimed to define the intracellular pathways of ROS-induced PARP-1 activation with ensuing cell death in lymphocytes. The results suggest that the mitogen-activated protein kinase ERK1/2 is involved in ROS-induced signal transduction and that ERK1/2 is activated upstream of PARP-1 in ROS-dependent lymphocyte parthanatos.