發(fā)布時(shí)間：2018-05-23 10:06

  本文選題：膠質(zhì)瘤免疫治療 + EFEMP1��； 參考：《南方醫(yī)科大學(xué)》2017年博士論文

【摘要】：神經(jīng)膠質(zhì)瘤也稱為膠質(zhì)瘤,為中樞神經(jīng)系統(tǒng)常見(jiàn)的神經(jīng)上皮性腫瘤,腫瘤多起源于神經(jīng)間質(zhì)細(xì)胞,包括神經(jīng)膠質(zhì)、室管膜、脈絡(luò)叢上皮及神經(jīng)元。對(duì)于神經(jīng)膠質(zhì)瘤的治療方式也不是一成不變的,需要綜合考慮腫瘤的起源部位、腫瘤體積大小及腫瘤性質(zhì)等因素,才能選擇并制定出最佳的治療方案。研究證明,促使膠質(zhì)瘤細(xì)胞生長(zhǎng)、增殖的主要原因是膠質(zhì)瘤細(xì)胞本身具有低免疫原性特點(diǎn),這也是膠質(zhì)瘤細(xì)胞能夠逃避機(jī)體免疫細(xì)胞的監(jiān)視及殺傷的主要原因;其次,神經(jīng)膠質(zhì)瘤細(xì)胞具有分泌免疫抑制因子的能力,這些免疫抑制因子可降低免疫細(xì)胞對(duì)腫瘤的殺傷效應(yīng)。因此,如何提高膠質(zhì)瘤細(xì)胞的免疫原性,促進(jìn)抗原提呈細(xì)胞對(duì)膠質(zhì)瘤抗原的識(shí)別,降低其發(fā)生“免疫逃逸”現(xiàn)象的幾率;如何阻止膠質(zhì)瘤細(xì)胞分泌免疫抑制因子,提高免疫細(xì)胞對(duì)膠質(zhì)瘤細(xì)胞的殺傷效率,這些都是膠質(zhì)瘤免疫治療的研究重點(diǎn)。EFEMP1,即fibulin-3蛋白,其主要分布在細(xì)胞表面及細(xì)胞之間,主要功能是參與調(diào)節(jié)細(xì)胞與組織之間的生理活動(dòng),穩(wěn)固細(xì)胞外基質(zhì)結(jié)構(gòu)完整。大量研究證明:EFEMP1參與并調(diào)節(jié)腫瘤細(xì)胞的生長(zhǎng)及運(yùn)動(dòng),在膠質(zhì)瘤與EFEMP1的相關(guān)性研究中發(fā)現(xiàn),通過(guò)對(duì)膠質(zhì)瘤細(xì)胞內(nèi)N ot c h信號(hào)通路和細(xì)胞內(nèi)基質(zhì)金屬蛋白酶的控制,EFEMP1可以間接的控制膠質(zhì)瘤細(xì)胞的生長(zhǎng)、增殖及向周?chē)M織侵襲的能力。因此我們提出了:可否通過(guò)抑制膠質(zhì)瘤細(xì)胞EFEMP1的表達(dá),從根本上降低膠質(zhì)瘤細(xì)胞的活力,降低膠質(zhì)瘤細(xì)胞對(duì)周?chē)ＤX組織侵襲的實(shí)驗(yàn)設(shè)想,本課題也以此作為實(shí)驗(yàn)研究展開(kāi)的關(guān)鍵切入點(diǎn)。樹(shù)突狀細(xì)胞(DCs)具有提呈膠質(zhì)瘤抗原并輔助CTL殺傷膠質(zhì)瘤細(xì)胞的重要功能。研究發(fā)現(xiàn):STAT蛋白家族成員中的STAT-3與樹(shù)突狀細(xì)胞的分化成熟關(guān)系密切。STAT-3活化水平的增加,可以抑制樹(shù)突狀細(xì)胞的分化成熟。抑制樹(shù)突狀細(xì)胞的STAT-3活性后,可解除IL-10、TGF、VEGF等因子對(duì)樹(shù)突狀細(xì)胞的免疫抑制;并能夠提高樹(shù)突狀細(xì)胞分泌細(xì)胞因子的水平。本課題擬將抑制膠質(zhì)瘤細(xì)胞EFEMP1表達(dá)與降低樹(shù)突狀細(xì)胞STAT-3表達(dá),兩種治療策略相結(jié)合。建立由EFEMP1低表達(dá)的膠質(zhì)瘤細(xì)胞荷瘤的動(dòng)物模型;利用慢病毒轉(zhuǎn)染方式降低樹(shù)突狀細(xì)胞的STAT-3表達(dá),制備出STAT3低水平表達(dá)的樹(shù)突狀細(xì)胞疫苗后,回輸至荷瘤動(dòng)物模型體內(nèi)。通過(guò)與對(duì)照組比較動(dòng)物模型的存活時(shí)間,荷瘤鼠膠質(zhì)瘤組織內(nèi)部淋巴細(xì)胞浸潤(rùn)、荷瘤鼠脾臟指數(shù)變化等實(shí)驗(yàn)指標(biāo),證實(shí)抑制膠質(zhì)瘤EFEMP1聯(lián)合低STAT-3表達(dá)的樹(shù)突狀細(xì)胞對(duì)于大鼠膠質(zhì)瘤的治療效果,為建立膠質(zhì)瘤的新型免疫治療策略提供理論支持。
[Abstract]:Glioma, also known as glioma, is a common neuroepithelial tumor in the central nervous system. Most of the tumors originate from nerve interstitial cells, including glia, ependyma, choroid plexus epithelium and neurons. The treatment of glioma is not inflexible. It is necessary to consider the origin of the tumor, tumor volume and tumor properties, in order to select and formulate the best treatment plan. It has been proved that the main reason for glioma cells to grow and proliferate is that glioma cells have low immunogenicity, which is the main reason that glioma cells can escape the surveillance and kill of immune cells. Glioma cells have the ability to secrete immunosuppressive factors which can reduce the killing effect of immune cells on tumor. Therefore, how to improve the immunogenicity of glioma cells, promote the recognition of glioma antigens by antigen-presenting cells, reduce the probability of "immune escape", and prevent glioma cells from secreting immunosuppressive factors, Increasing the killing efficiency of immune cells to glioma cells is the focus of immunotherapy of glioma. EFEMP1, or fibulin-3 protein, mainly distributes on the surface of glioma cells and between cells. The main function is to regulate the physiological activities between cells and tissues and to stabilize the structure of extracellular matrix. A large number of studies have shown that: EFEMP1 is involved in and regulates the growth and motility of tumor cells, and has been found in the study of the relationship between glioma and EFEMP1. Through the control of N ot c h signaling pathway and matrix metalloproteinases in glioma cells, EFEMP1 can indirectly control the growth, proliferation and invasion of glioma cells to surrounding tissues. Therefore, we propose a tentative idea of whether we can reduce the activity of glioma cells and the invasion of glioma cells to normal brain tissues by inhibiting the expression of EFEMP1 in glioma cells. This topic also takes this as the key breakthrough point of the experimental research. Dendritic cells (DCs) play an important role in presenting glioma antigens and assisting CTL in killing glioma cells. It was found that STAT-3 in the member of the protein family of 1: STAT was closely related to the differentiation and maturation of dendritic cells. The increase of activation level of STAT-3 could inhibit the differentiation and maturation of dendritic cells. Inhibiting the STAT-3 activity of dendritic cells could relieve the immunosuppressive effect of IL-10 TGF- STAT-3 on dendritic cells and increase the level of cytokines secreted by dendritic cells. The aim of this study is to combine the inhibition of EFEMP1 expression in glioma cells and the reduction of STAT-3 expression in dendritic cells. An animal model of glioma cells with low expression of EFEMP1 was established, the STAT-3 expression of dendritic cells was reduced by lentivirus transfection, and the dendritic cell vaccine with low expression of STAT3 was prepared, and then injected back into the tumor-bearing animal model. Compared with the control group, the survival time of the animal model, the infiltration of lymphocytes in glioma tissue and the change of spleen index in tumor-bearing mice were measured. It is confirmed that the inhibitory effect of EFEMP1 combined with low STAT-3 expression of dendritic cells on rat glioma provides theoretical support for the establishment of a new immunotherapy strategy for glioma.
【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R739.41

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