基于大肠杆菌粘附素FimH开发抗癌症免疫治疗的新型佐剂

Cancer is a heterogeneous disease that results from a multi-step process, characterized by uncontrolled tumor cell proliferation, invasion and metastasis. Despite improvements in diagnosis and therapies, cancer is still the most fatal disease worldwide. As an emerging cancer treatment, immunotherapy has drawn more and more attention from scholars. The induction of antigen (Ag)-specific immune activation by the maturation of dendritic cells (DCs) is one strategy for immunotherapy against cancer. Although scientists are well known that the induction of Ag-specific immune activation is important, there is still limitation for the induction of immune responses, since lack of effective adjuvant..Based on our previous findings, we hypothesize that Escherichia coli (E. coli) adhesion portion protein FimH is expected to have great potential as a novel adjuvant in immunotherapy against cancer. Therefore, we will examine FimH in the induction of TLR4-dependent DCs activation in tumor-bearing mice in vivo by flow cytometry, ELISA and ELISPOT. Moreover, we will define adjuvant effect of FimH against cancer by a combination treatment of cancer Ag and FimH. Finally, we will evaluate mucosal adjuvant effect of FimH against lung metastasis model of cancer. We believe that we can successfully evaluate the effect of FimH as an adjuvant and it will be able to use for immunotherapy molecule against cancer.

长期以来，癌症被认为是全球范围内最致命的疾病之一。免疫疗法作为一种新兴的癌症治疗手段已引起学者们越来越广泛地关注。通过诱导树突状细胞的成熟引发的抗原特异性免疫反应是癌症免疫治疗的一种有效途径，然而有效佐剂的缺乏是这一治疗途径的主要限制因素。基于前期的研究结果，我们推测大肠杆菌粘附素FimH蛋白有望作为一种新型的佐剂在抗癌症的免疫治疗中发挥极大应用潜力。因此，本项目拟以肿瘤小鼠为研究对象，通过流式细胞术、ELISA、ELISPOT等方法在体内探究FimH对树突状细胞的活化作用以及该过程与TLR4的依赖关系，进而通过探究FimH结合癌症抗原给药所引发的抗原特异性免疫反应明确FimH抗癌症的佐剂效应。在此基础上，我们将进一步探究FimH对模型小鼠肿瘤肺转移的抑制效果，并评价其黏膜佐剂的功效，以期从多角度阐明FimH作为佐剂的免疫学机理，为癌症的免疫治疗提供新的药物候选以及理论依据。

长期以来，癌症被认为是全球范围内最致命的疾病之一。免疫疗法作为一种新兴的癌症治疗手段已引起学者们越来越广泛地关注。通过诱导树突状细胞的成熟引发的抗原特异性免疫反应是癌症免疫治疗的一种有效途径，然而有效佐剂的缺乏是这一治疗途径的主要限制因素。基于前期的研究结果，本项目在小鼠体内证明FimH处理可有效诱导相应DCs亚群的活化，并通过增强Th1和Tc1细胞发挥作用，同时利用基因敲除小鼠证明FimH对DCs的活化依赖TLR4但不依赖于MD2。通过肿瘤模型小鼠证明FimH可有效诱导抗原特异性T细胞增殖和免疫应答，抑制小鼠体内肿瘤细胞的生长。此外，FimH可通过黏膜途径诱导DCs活化，并进而促进抗原特异性T细胞增殖，与肿瘤抗原联合作用可显著抑制小鼠肺部肿瘤生长。本课题围绕大肠杆菌粘附素FimH在动物模型中多方面、多角度证明其作为抗肿瘤免疫佐剂的作用，为基于DCs的癌症免疫治疗提供新的佐剂候选以及实验依据。