Suppression of the innate anti-bacterial response in Chronic Lymphocytic Leukemia

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Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in the Western hemisphere. It is associated with severe infections and 60% of the CLL patients even succumb to these infections. Given that the immune response against infections depends on neutrophils, this proposal investigates the mechanisms that suppress neutrophil responses in CLL. Preliminary experiments revealed an increased mortality in CLL mice that have been challenged with a bacterial infection. Moreover, the phagocytic function of neutrophils was diminished in CLL mice. Transcriptomic analyses of neutrophils isolated from CLL mice revealed increased activity of the TGFb-receptor signalling suggesting a potential mechanism for the suppressed neutrophil response and severe infections in CLL.This proposal will investigate how neutrophil responses are suppressed in CLL. Given that we have identified the TGFb-receptor pathway in our preliminary experiments, we will target this receptor specifically in neutrophils to evaluate the role of this receptor for the suppressed neutrophil response. We also aim at identifying novel target molecules in neutrophils beyond the TGFb-receptor by performing proteomic analyses of neutrophils isolated from CLL mice. Finally, we will translate our findings into the human situation by isolating neutrophils from the blood of CLL patients, which have not received anti-tumor agents yet. We will perform proteomic and functional analyses of these neutrophils to investigate the mechanisms of neutrophil-suppression also in CLL patients. These findings will also be compared to the murine datasets of this proposal to identify overarching mechanisms of neutrophil suppression in CLL. These findings might also contribute to the development of novel strategies against severe infections in CLL patients.