HDAC7在内皮祖细胞介导的肺癌血管新生及免疫抑制中的作用及机制探讨

Angiogenesis and immunosuppression in invasion and metastasis of NSCLC has been recognized. We and studies confirmed that endothelial progenitor cells (EPCs) and myeloid-derived suppressor cells (MDSCs) participated in this process of angiogenesis and immunosuppression of NSCLC. We has found that inhibiting HDAC7 could impair EPCs mediated angiogenesis in NSFC for the first time. Preliminary study suggested that the EPCs were injected through tail vein in animal experiments, and the number of CD11b+ cells was increased. After inhibiting the expression of HDAC7 in EPCs, the CD11b+ cells in the tumor were significantly reduced. According to this phenomenon, so we assume that: HDAC7 and its downstream molecular recruited EPCs in bone marrow to participate in promoting the angiogenesis of NSCLC, at the same time EPCs increased the number of MDSCs through direct (directional differentiation) and indirect (raise, secreted cytokines induced differentiation) ways in tumor microenvironment to playing immunosuppressive function. This project will further clarify the mechanism of HDAC7 participating in angiogenesis and immunosuppression, providing a new strategy for HDAC inhibitors (targeting HDAC7) in improving immune treatment effectiveness and anti-angiogenesis therapy.

“血管新生”与“免疫抑制”参与肺癌的浸润转移过程已得到公认。我们和国内外研究证实：内皮祖细胞及骨髓来源抑制细胞参与肺癌的血管新生及免疫抑制进程。申请人在国家自然科学基金青年基金的研究中首次发现：抑制HDAC7可以从多方面抑制内皮祖细胞介导的血管形成能力。前期研究提示：动物实验中通过外源性输入内皮祖细胞，瘤体中具有骨髓来源抑制细胞表型的细胞数量明显增多。抑制内皮祖细胞中HDAC7表达后，瘤体中骨髓来源抑制细胞明显减少。根据这一现象因此我们假设：HDAC7及其下游的效应分子激活骨髓中内皮祖细胞参与促进肺癌的血管新生，同时通过内皮祖细胞直接（定向分化）及间接（分泌细胞因子诱导募集，分化）作用促使肺癌微环境中骨髓来源抑制细胞的增多从而发挥免疫抑制功能。本项目将进一步阐明HDAC7参与血管新生及免疫抑制的机制，为以HDAC7为靶点的HDAC抑制剂抑制肺癌的血管新生及免疫抑制活动，发挥增进免疫治疗疗。

“血管新生”与“免疫抑制”参与肿瘤的浸润转移过程已得到公认。本研究在前期发现HDAC7维持内皮祖细胞EPCs的结构性和非结构性功能的分子机制基础上，动物实验中通过外源性输入鼠源内皮祖细胞，瘤体中具有骨髓来源抑制细胞表型的细胞数量明显增多。通过抑制内皮祖细胞中HDAC7表达后，瘤体中骨髓来源抑制细胞明显减少。HDAC7及其下游的效应分子激活骨髓中内皮祖细胞参与促进肿瘤的血管新生，同时通过内皮祖细胞间接(分泌细胞因子诱导募集， 分化)作用促使肿瘤微环境中骨髓来源抑制细胞的增多从而发挥免疫抑制功能。本项目进一步阐明HDAC7参与血管新生及免疫抑制的机制，为以HDAC7为靶点的HDAC抑制剂抑制肿瘤的血管新生及免疫抑制活动提供理论依据。