Embelin对髓系来源抑制性细胞的调控机制及其在炎症相关性结直肠癌中的作用

髓系来源抑制性细胞(MDSCs)抑制抗肿瘤免疫应答，促进结直肠癌发生和进展，并与抗VEGF靶向治疗耐药相关。我们前期发现信筒子素(Embelin)可抑制小鼠炎症相关性结直肠癌，机制与对肿瘤免疫微环境的调节有关。Embelin还可减少荷瘤小鼠肿瘤中MDSCs，并影响其它免疫细胞数量和功能。基于MDSCs在肿瘤微环境中的重要作用，推测炎症相关性结直肠癌中Embelin可能通过调控MDSCs发挥抗肿瘤作用。本研究拟体外探讨Embelin对MDSCs聚集、增殖和活化的直接调控作用；及通过MDSCs对T细胞增殖及功能、对Th17细胞分化及对巨噬细胞表型转化的影响及机制。研究Embelin对炎症相关性结直肠癌小鼠体内MDSCs数量和功能的影响，及与肿瘤发生进展的关系。探讨Embelin是否通过对MDSCs的抑制而增强抗VEGF靶向治疗效果，阐明二者联合应用的协同作用。为探寻结直肠癌防治新策略提供依据。

Chronic colonic inflammation promotes the accumulation of myeloid-derived suppressor cells (MDSCs) that down-regulate immune surveillance and antitumor immunity, thereby facilitating tumor growth. Infiltration of the tumor tissue by MDSCs is associated with inherent anti-VEGF refractoriness. Our previous studies have showen that embelin effectively suppressed AOM/DSS induced colitis-associated tumorigenesis in mice, and its antitumor effect was partly mediated by modulating immune response. Meanwhile, embelin reduced MDSCs recruitment in CT26WT tumor-bearing mice. We therefore speculate that embelin inhibits colitis-associated tumorigenesis by limiting MDSCs function. In this study, we aim to elucidate the effects of embelin on the recruitment, expansion, and activation of MDSCs. In addition, we will investigate the in vivo effects of embelin on immune function in colitis associated cancer-bearing mice to examine if a favorable immunomodulatory effect accompanies tumor suppression, with a particular focus on their ability to modulate T-cell responses and the phenotype of macrophages. Furthermore, we will test therapeutic regimen combining embelin and anti-VEGF treatment to examine a synergistic effect on tumor growth. The results will deepen our understanding into the role of embelin in regulating the MDSCs in colitis-associated tumorigenesis. The insight gained from this study will facilitate the development of novel therapeutic approaches for colorectal cancer.