血管内皮抑制素调控髓系抑制性细胞的分化及功能的作用机制研究

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.

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。

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。本课题主要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。本课题为一年度研究计划，根据计划任务书要求，我们已经完成血管内皮抑制素对肺癌患者MDSC 频率、数量及表型的影响，以及体外血管内皮抑制素对MDSC 的扩增、分化、存活及功能的调节作用。研究结果表明肺癌患者血液中MDSC的表型主要为CD14+HLA-DR-，应用血管内皮抑制素治疗的肺癌患者血液中MDSC的频率显著下调、数量绝对值也显著下降。进一步体外实验发现，在体外MDSC诱导培养扩增过程中，添加血管内皮抑制素可以有效抑制MDSC的扩增，促进MDSC的凋亡;同时可以抑制MDSC的免疫抑制功能；但对MDSC的分化无显著影响。具体的作用分子仍不清楚，有待后续实验进一步阐明。目前已经完成一年期研究计划的实验数据整理以及论文撰写，完成一名研究生培养。