髓系抑制性细胞（MDSC）是近年来发现的一群免疫抑制细胞，其在肿瘤免疫逃逸中发挥重要作用。血管抑制素为近年来应用于临床的重要抗肿瘤血管生成药物，我们前期在应用该类药物恩度治疗肺癌时发现，患者血液中以CD14+HLA-DR-为标志的MDSC数量及比例显著下降；体外实验发现恩度不但可以有效阻断MDSC介导的T细胞应答抑制功能，还能直接诱导该群细胞的凋亡。这些结果提示我们血管内皮抑制素可能在MDSC的分化、扩增中发挥重要的作用。目前关于血管抑制素对免疫系统的调节功能国内外均未见相关报道。本课题拟研究血管内皮抑制素对MDSC的表型、分化、扩增、存活以及功能的影响。本研究将为MDSC的生成及功能调节提供新的分子机制。

Recently, accumulating evidence has shown that a population of cells with suppressive activity (known as myeloid-derived suppressor cells (MDSCs)) contributes to the negative regulation of immune responses during cancer and other diseases. However, the mechanism by which regulates the population generation and death remains largely unclear. Endostatin is an important endogenous inhibitor of neovascularization that has been widely used in anti-angiogenesis therapy for the treatment of cancer. Our preliminary work showed that the frequency and number of MDSC,defined by CD14+HLA-DR-, were significantly increased in blood from the patient of lung cancers. However, the population was decreased after endostatin treatment.Moreover, we found that endostatin could effectively induced MDSC apoptosis,which suggested that endostatin might be involved in MDSC generation，death or function. So far, there is little information regarding the effect of endostatin on immune system. Thus, in this proposal, firstly, we will determine the the phenotype and function of MDSCs from the patients with lung cancer, and the effect of endostatin on MDSC frequency and number in blood and tumor sites. Secondly,by in vitro assay, we investigate the effect of endostatin on MDSC differentiation, expansion, survival and immune-suppressive function. Through this study we aim to elucidate the function and signalling mechanism of endostatin in the generation or death of MDSCs, and open a new avenue for the anti-tumor therapy of endostatin.