荷瘤状态下中性粒细胞的信号途径调控机制研究

中性粒细胞（PMN）是肿瘤微环境中大量存在的免疫细胞。虽然PMN具有抗肿瘤潜能，但肿瘤微环境中的PMN却不能产生抑瘤效应，反而具有促瘤作用。我们在研究中发现，肿瘤产生的G-CSF和IL-6使骨髓PMN产生促瘤功能。同时观察到，荷瘤状态改变了骨髓PMN的反应特性，使PMN的STAT3激活水平升高，而在受到肿瘤组织间液分子刺激时，PI3K和p38MAPK途径不能有效激活；体内表达G-CSF和IL-6亦产生同样效应。STAT3、PI3K、p38MAPK是影响PMN促瘤与抗瘤潜能的关键信号途径，本项目研究中，将着重探讨G-CSF和IL-6协同调控这些信号途径的相关机制，同时还将研究干扰素和TNF-α恢复PMN反应性的作用。本项目研究可从信号途径激活调控的角度阐明PMN激活的控制机制，不仅具有重要的理论价值，而且可为建立荷瘤状态下有效激活PMN的策略、利用PMN治疗肿瘤的研究提供新的思路和依据。

Polymorphonuclear leukocytes (PMNs or neutrophils) make up a significant portion of the inflammatory cell infiltrate found in a wide variety of human cancers and murine models. Neutrophils have the potential to suppress tumor growth through their cytotoxicity against tumor cells and cause the damage of vascular endothelium by producing oxidants and releasing proteolytic enzymes. In contrast, however, in recent years studies have begun to emerge showing critical roles of neutrophils in tumorigenesis. There are compelling data that neutrophils have significant protumor actions, and that they are key mediators of tumor angiogenesis..In our recent studies, we found that tumor-derived G-CSF and IL-6 could augment the protumor potential of neutrophils. Our data showed that tumor burden altered the function and response of neutrophils, characterized by increased activation level of STAT3 in neutrophils, and the inefficient activation of PI3K and p38MAPK pathways in neutrophils in response to the stimuli in tumor milieu. Moreover, in vivo expression of G-CSF and IL-6 in absence of tumor showed same effect on neutrophils. STAT3, PI3K, and p38MAPK pathways are crucial signaling pathways which influence the anti- and pro-tumor potential of neutrophils. In this project, we will investigate the mechanisms underlying the modulatory effect of G-CSF and IL-6 on the function of neutrophils, especially on the activation of these signaling pathways. Meanwhile, we will also investigate whether IFN-β, IFN-γ and TNF-α could recover the response of neutrophils based on the modulation of G-CSF and IL-6. .Although there are compelling data indicate a deleterious role of neutrophils in tumor progression, therapeutically targeting this cell type in cancer is fraught with difficulties. Neutrophils are critical mediators of host defense against infection, and depletion of these cells could result in dangerous levels of immunosuppression. Our study will try to elucidate the mechanism underlying the regulation of neutrophil activation. The results may not only be important for the theory of immunoregulation, but also lead to the new strategy of tumor therapy by recovering the anti-tumor function of neutrophils in presence of tumor.