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

慢性淋巴细胞白血病(CLL)是西半球最常见的白血病类型。它与严重感染有关，60%的慢性淋巴细胞性白血病患者甚至死于这些感染。鉴于对感染的免疫反应依赖于中性粒细胞，这项建议研究了CLL中抑制中性粒细胞反应的机制。初步实验显示，受到细菌感染的CLL小鼠的死亡率增加。此外，CLL小鼠中性粒细胞的吞噬功能减弱。从CLL小鼠分离的中性粒细胞的转录分析显示，TGFb受体信号的活性增加，这可能是CLL中性粒细胞反应受抑和严重感染的潜在机制。这项建议将研究CLL中中性粒细胞反应是如何被抑制的。鉴于我们已经在初步实验中确定了TGFb受体途径，我们将针对中性粒细胞中的这一受体来评估该受体在抑制中性粒细胞反应中的作用。我们还旨在通过对从CLL小鼠分离的中性粒细胞进行蛋白质组学分析，识别TGFb受体以外的中性粒细胞中的新靶分子。最后，我们将通过从CLL患者的血液中分离中性粒细胞将我们的发现转化为人类情况，这些患者尚未接受抗肿瘤药物治疗。我们将对这些中性粒细胞进行蛋白质组学和功能分析，以探讨CLL患者中性粒细胞抑制的机制。这些发现也将与这项建议的小鼠数据集进行比较，以确定CLL中中性粒细胞抑制的主要机制。这些发现也可能有助于开发针对CLL患者严重感染的新策略。

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.