IL-33抑制乳腺癌向肺部转移及其机制研究

发布时间：2018-03-08 10:13

本文选题：IL-33　切入点：乳腺癌转移　出处：《中国科学技术大学》2017年博士论文　论文类型：学位论文

【摘要】：IL-33是IL-1家族的成员,是细胞内源性警报素,由坏死或凋亡的上皮和内皮细胞表达释放。IL-33的信号传导依赖于细胞膜上的特异性受体ST2L,主要表达于免疫细胞。IL-33在先天免疫和获得性免疫中具有重要作用,同时还参与调节组织的内稳态以及应对环境压力。IL-33在不同疾病中通过不同免疫学机制发挥其双功能性作用:如通过促进Th2型免疫反应,参与过敏哮喘和关节炎等Th2相关的疾病;而在炎症相关的动脉硬化和感染诱导的组织损伤中起保护作用。IL-33在肿瘤中作用的研究报道不一:一方面通过促进MDSC、TAM等免疫抑制细胞增生,促进乳腺癌和结肠癌生长或转移;而另一方面利用IL-33转基因小鼠、肿瘤细胞高表达IL-33或者将IL-33作为免疫佐剂,可促进CD8~+T、NK细胞肿瘤侵润,ILC2增殖或激活DC,从而抑制肿瘤的生长和转移。肿瘤的转移是导致治疗失败和复发的最主要原因,而化疗是目前最广泛用来控制术后肿瘤转移的治疗手段。前期对接受化疗病例的血清检测中发现,由于化疗对细胞杀伤,导致IL-33表达显著升高。为此,本文利用乳腺癌转移小鼠模型,探究IL-33在肿瘤转移中的作用和可能机制。本研究利用携带荧光素酶的高转移乳腺癌细胞系,经尾静脉注射构建肿瘤转移模型,给予基因重组IL-33,发现IL-33可显著抑制乳腺癌肿瘤的肺部转移。系统性的免疫细胞分析发现:IL-33可显著促进脾脏和肺脏中CD8~+T、NK、B、ILC2和嗜酸性粒细胞数量;同时细胞因子IL-5、IFNγ、趋化因子CCL5的表达量也明显上升。利用IL-33特异性受体ST2全基因敲除小鼠肿瘤转移模型的研究证明,IL-33通过免疫细胞上ST2信号通路调节免疫应答从而发挥抑制肿瘤生长和转移的作用。分别利用IL-5和CD8抗体清除小鼠体内嗜酸性粒细胞和CD8~+T细胞可一定程度上减弱肿瘤转移;当同时清除嗜酸性粒细胞和CD8~+T细胞时,则显著扭转了 IL-33抑制肿瘤肺部转移的作用。研究结果显示,IL-33通过促进ILC2分泌IL-5调节嗜酸性粒细胞增生,同时促进CD8~+T细胞募集的协同作用起到抑制癌细胞肺转移的作用,为IL-33作为肿瘤免疫治疗的细胞因子提供了理论依据。
[Abstract]:IL-33 is a member of the IL-1 family. The signal transduction of IL-33 released by necrotic or apoptotic epithelium and endothelial cells is dependent on the specific receptor ST2L. it is mainly expressed in immune cells. IL-33 plays an important role in innate and acquired immunity. IL-33 is also involved in regulating the homeostasis of tissues and coping with environmental stress. IL-33 plays a dual functional role in different diseases through different immunological mechanisms: for example, by promoting Th2 type immune response, participating in allergic asthma and arthritis and other Th2 related diseases; However, there are different studies on the role of IL-33 in tumour by promoting the proliferation of immunosuppressive cells such as MDSC-TAM and promoting the growth or metastasis of breast cancer and colon cancer by promoting the proliferation of immunosuppressive cells, such as MDSC-TAM, which play a protective role in inflammation related arteriosclerosis and infection-induced tissue damage. On the other hand, using IL-33 transgenic mice, tumor cells overexpression IL-33 or use IL-33 as immune adjuvant, It can promote the proliferation of CD8 ~ TnNK cell tumor invading ILC2 or activate DC. so it can inhibit the growth and metastasis of tumor. The metastasis of tumor is the main cause of failure and recurrence of treatment. At present, chemotherapy is the most widely used method to control the metastasis of tumor after operation. In the early detection of serum of patients receiving chemotherapy, it was found that the expression of IL-33 was significantly increased due to the cytotoxicity of chemotherapy. In this study, the role and possible mechanism of IL-33 in tumor metastasis were investigated by using mouse model of breast cancer metastasis. In this study, tumor metastasis model was established by intravenous injection of high luciferase carrying breast cancer cell line. It was found that IL-33 could significantly inhibit the lung metastasis of breast cancer. The systemic immunocytic analysis showed that: IL-33 could significantly promote the number of CD8 ~ TNKBmBmC2 and eosinophilic granulocytes in spleen and lung. At the same time, the expression of cytokine IL-5, IFN- 纬 and chemokine CCL5 was also significantly increased. The study of tumor metastasis model of IL-33 specific receptor ST2 knockout mice demonstrated that IL-33 regulates immune response through ST2 signaling pathway in immune cells. IL-5 and CD8 antibodies were used to remove eosinophils and CD8T cells in mice to some extent. When both eosinophils and CD8T cells were removed simultaneously, the inhibitory effect of IL-33 on lung metastasis was significantly reversed. The results showed that IL-33 regulated eosinophil proliferation by promoting the secretion of IL-5 by ILC2. At the same time, the synergistic effect of promoting the recruitment of CD8T cells inhibits lung metastasis of cancer cells, which provides a theoretical basis for IL-33 as a cytokine for tumor immunotherapy.
【学位授予单位】：中国科学技术大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R737.9

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