The Impact Of Oxidative Stress On The Immune Compartment Of Chronic Lymphocytic Leukemia Patients

Reactive oxygen species (ROS) such as hydrogen peroxide or superoxide are highly reactive and hyperpermeable. They are continuously produced by mainly the mitochondria during oxidative phosphorylation. Immune cells of especially myeloid origin contribute additionally to the ROS production via the membrane-bound NADPH-oxidase. During inflammation or “inflammatory-like” conditions as often seen in neoplasias ROS production is highly increased. The physiological redox-buffers are overwhelmed leading to the metabolic condition termed oxidative stress. Immune cells, especially NK- and T-cells are very sensitive towards ROS-induced cell death resulting from mitochondrial depolarization. Furthermore, ROS can interfere with nuclear NF-kB translocation thus leading to reduced activation, cytokine production, and cytotoxic activity of immune cells. Functional immune defects at several levels as well as significant shifts in the balance of immune populations have been related to oxidative stress in patients suffering from mainly solid malignant diseases. In this study we sought out to investigate the presence of oxidative stress in patients with chronic lymphocytic leukemia (CLL) and its potential effects on their cellular immune compartment.

Peripheral blood and serum from 65 patients with untreated CLL was collected upon informed consent. Oxidative stress was measured based on the concentration of so-called ROS-surrogate markers in the patients' sera. Therefore oxidized lipids, proteins, and DNA bases were quantified by ELISA. The immune compartment was evaluated using multicolor flow cytometry and the analyses included T-, NK-, myeloid-, and dendritic-cell subsets.

ROS levels were increased in CLL patients. Based on the concentration of ROS-modified molecules we were able to group our patient cohort into a ROS^hi and ROS^lo group. The ROS^hi group exhibited lower levels of T-cell activation, while there was a shift of the CD56^bright/CD56^dim NK-cell balance towards the CD56^bright subset. We could not detect significant differences in the myeloid- and dendritic-cell compartment or alterations of T- and NK-cell maturation.

Our results implicate that ROS belongs to the tumor immune escape mechanism present in CLL. The use of redox modifying agents in combination with the steadily emerging immune-based approaches could potentially boost their therapeutic efficacy.