GMP-CA125免疫原性和抗上皮性卵巢癌的免疫应答研究

Tumor-associated antigen (TAA) had the low immunogenicity and weak ability to drive the anti-tumor immune response. In order to improve the immunogenicity of TAA, it needed to promote antigen-presenting cells (APCs) to take up TAA and more mature dendritic cells (DCs) to present TAA to T cells to achieve specific anti-tumor immune response. In our prophase research, we prepared hollow and porous beta glucan particles (GMP) from cell walls of baker's yeast which was easy to be taken up by the DCs and macrophages and could carry protein fragment to promote mature DCs. CA125 was known as the repeat peptides of the mucin MUC16 which was expressed on the surface of epithelial ovarian cancer and contained many antigenic determinant. CA125 had been shown to play roles in mediating the humoral immune response. The immunofluorescence proved its high expression in ovarian cancer tissue sections in our early results.. The research will use GMP loaded CA125(GMP-CA125) peptides to study its ability of promoting mature DCs and driving anti-tumor immune response of specific T cells. GMP-CA125 could enhance immunogenicity and drive specificity anti-tumor immune response of CA125 through the immune stimulation function of GMP. Here, we tried to provide an effective way for immunotherapy in epithelial ovarian cancer and clues for preparation of DC vaccines in other malignant tumors.

肿瘤相关抗原（TAA）免疫原性低，驱动抗瘤免疫反应能力弱。为了提高TAA的免疫原性，需要促进抗原递呈细胞（APCs）吞噬TAA，更要促进树突状细胞（DCs）成熟，才能递呈TAA给T细胞，实现特异性抗瘤免疫反应。课题组在前期研究中制备的来源于酵母中空多孔β-葡聚糖颗粒（GMP）容易被DCs和巨噬细胞吞噬，且能装载蛋白片段促进DCs成熟。CA125是表达于上皮性卵巢癌细胞表面的粘蛋白MUC16分子肽段，含有许多抗原决定簇，能驱动体液免疫反应，前期免疫荧光证明其在原发癌组织切片上高表达。. 本研究将用GMP负载CA125(GMP-CA125)，研究其促进DC成熟和驱动特异性T细胞抗瘤免疫反应的能力。GMP-CA125可借助GMP免疫刺激功能提高CA125的免疫原性，驱动CA125特异性抗瘤免疫反应，尝试为上皮性卵巢癌的免疫治疗提供有效途径，也能为其他恶性肿瘤DC疫苗的制备提供线索。

卵巢癌起病隐匿其致死率居妇科恶性肿瘤首位。临床试验发现卵巢癌是一种对免疫治疗敏感的癌种。理论上提高肿瘤相关抗原（TAA）的免疫原性就有可能实现特异性抗瘤免疫反应。CA125是表达于上皮性卵巢癌细胞表面的粘蛋白MUC16分子肽段，含有许多抗原决定簇，能驱动体液免疫反应。本研究以 CA125 作为靶点进行上皮性卵巢癌免疫治疗的实验研究，以来源于酵母中空多孔β-葡聚糖颗粒（GMP）为载体建立了一种载药体系GMP-CA125的制备及检测方法，蛋白质包封效率为51.71±2.62 %，体外研究显示该载药颗粒容易被免疫细胞吞噬且能被巨噬细胞选择性吞噬，能促进DC成熟、提高DCs的抗原递呈能力，但是体外的特异性试验验证和体内抑瘤实验结果不理想，需要调整体系方案继续实验。我们认为该体系可高选择性输送各种蛋白到免疫细胞，在靶向药物给药和在DC细胞疫苗设计方面有广泛的应用前景。该体系可为上皮性卵巢癌的免疫治疗提供可选途径，也能为其他恶性肿瘤DC疫苗的制备提供线索。