玉屏风散调控髓系来源抑制性细胞重塑肺癌免疫微环境的分子机制研究

Anti-Cancer Cellular Immunotherapy is an effective method for treatment of lung cancer. The immune microenvironment intervention has become a research hotspot. Myeloid-derived suppressor cells (MDSCs) are the main cells mediated tumor immune escape and inhibit the body's immune. They have a close relation with poor prognosis of lung cancer. Early studies have shown that YuPingFengSan(YPFS) could reduce the quantity of MDSCs of Lewis lung cancer a tumor-burdened rat, and increase the quantity and activity of Natural killer cells and T cells. We found that YPFS significantly inhibited tumor of LLC- bearing mice growth compared to untreated control. we further study found that YPFS could reduce the main genes expression of the signal pathways of JAK-STAT and NF-κB in MDSCs. Then we propose a hypothesis that YPFS regulating the signal pathways of JAK-STAT and NF-κB of MDSCs to reshaping the immune function in tumor microenvironment to inhibiting the immunity escapes. Such as whole, cell and molecules levels by taking advantage of Lewis lung cancer model and co-culture system of MDSCs with T cells or NK cells or lung cancer cells in vitro,adopting microfluidic technology, imaging technology in vivo, flow cytometry, Gene overexpression, RNA interference technology,IHC and so on. This subject will reveal the molecular mechanism of the effect to MDSCs and the signal pathways of JAK-STAT and NF-κB under intervention of this YPFS in lung cancer microenvironment, provide the basis for clinical application.

干预微环境免疫逃逸为基础的免疫靶向治疗已证实对肺癌确有效疗，免疫微环境干预迅速成为研究热点。髓系来源抑制性细胞(MDSCs)能显著抑制肿瘤特异性免疫，是介导肿瘤免疫逃逸主要细胞群体,与肺癌不良预后密切相关。前期研究显示玉屏风散有抑瘤、延长生存期、增强NK和T 细胞功能，下调MDSCs数量及与JAK/STAT和NF-κB通路相关的细胞因子。据此提出“玉屏风散通过JAK/STAT和NF-κB信号通路调控MDSCs重塑肺癌免疫微环境抑制免疫逃逸”的假说。课题采用Lewis肺癌模型及体外MDSCs和肺癌细胞、NK和T细胞共培养体系,运用活体成像技术、流式细胞术、基因过表达、RNA干扰、免疫组化等技术，观察玉屏风散对上述信号通路及MDSCs的作用，从整体、细胞、分子等多层次揭示玉屏风散对上述信号通路调控MDSCs分子机制及作用靶点，从肿瘤微环境免疫编辑角度阐明扶正抗癌分子机理，为临床应用提供依据。

干预微环境免疫逃逸为基础的免疫靶向治疗已证实对肺癌确有效疗，免疫微环境干预迅速成为研究热点。髓系来源抑制性细胞(MDSCs)能显著抑制肿瘤特异性免疫，是介导肿瘤免疫逃逸主要细胞群体，与肺癌不良预后密切相关。本研究显示玉屏风散具有延缓肿瘤生长、延长荷瘤鼠生存期、增强机体NK和T细胞功能，下调MDSCs数量及与JAK/STAT和NF-κB通路相关的细胞因子。课题采用Lewis肺癌模型及体外MDSCs和肺癌细胞、NK和T细胞共培养体系，观察玉屏风散对上述信号通路及MDSCs的作用，从整体、细胞、分子等多层次揭示玉屏风散对上述信号通路调控MDSCs分子机制及作用靶点，明确了（1）玉屏风散能抑制肺癌小鼠皮下移植瘤的生长，参与调控MDSCs细胞的增殖及活化；（2）玉屏风散通过调控MDSCs功能抑制肺癌细胞的增殖、迁移及侵袭。（3）玉屏风散通过IL-1β/NF-κB信号通路抑制MDSCs增殖和活化而重塑肺癌免疫微环境。从肿瘤微环境免疫编辑角度阐明扶正抗癌分子机理，为临床应用提供依据。