重组幽门螺旋杆菌中性白细胞激活蛋白（rMBP-NAP）靶向肿瘤微环境的抗肿瘤作用及机理研究

The tumor microenvironment may promote tumor formation and metastasis.mainly via angiogenesis induction, suppression of immune surveillance and immune response and breeding tumor stem cells. Compared with the conventional cancer therapeutic method, targeting therapy of tumor microenvironment such as antiangiogenesis and immunotherapy of tumor is more efficient and low toxic, and is considered as the novel therapeutic option for cancer. The neutrophil-activating protein of helicobacter pylori (HP-NAP) is able to redirect Th2 into Th1 responses by eliciting neutrophils and monocytes to produce IL-12 and IL-23 and is confirmed as a immunomodulatory agent enhancing Th1 response. As tumor immune escape and tolerance are closely related to Th1/Th2 shifting, HP-NAP may possess the potential on cancer treatment. However, the anti-tumor effect of HP-NAP is seldom reported and the mechanism of action is unclearly. In this project, the anti-tumor effect of recombinant Helicobacter pylori neutrophil-activating protein (rMBP-NAP) targeting the tumor microenvironment, will be first investigated in various marine tumor model with different dose schedule and then the interaction mechanisms between the immunologic adjustment and antiangiogenesis of rMBP-NAP will be explored. It will lay the foundation for rMBP-NAP used as an anti-tumor candidate drug targeting the tumor microenvironment and provide theoretic direction for the use of rMBP-NAP in combination with other anti-tumor drugs for cancer therapy.

肿瘤微环境可促进肿瘤的发生和转移。相对于传统的肿瘤治疗方法，靶向肿瘤微环境的治疗方法具有高效、低毒以及广谱的优势，而被认为可能为抗肿瘤治疗提供新的选择。幽门螺旋杆菌中性白细胞激活蛋白（HP-NAP）能通过诱导人中性粒细胞和单核细胞产生IL-12和IL-23，进而逆转Th1/Th2漂移，被认为是增强Th1型反应的免疫调节剂。由于Th1/Th2漂移与肿瘤逃逸和肿瘤免疫耐受密切相关，且IL-12和IL-23可通过多种作用抑制肿瘤生长，因而HP-NAP是值得关注的靶向肿瘤微环境的候选抗肿瘤药物。然而目前有关HP-NAP抗肿瘤作用的研究还罕有报道并且其作用机制也不完全清楚。本课题首先在不同的肿瘤模型上，研究HP-NAP重组融合蛋白(rMBP-NAP)靶向肿瘤微环境的抗肿瘤作用，并进一步阐明其作用机制网络，并为rMBP-NAP与其它抗肿瘤药的联合使用提供理论依据。

幽门螺旋杆菌中性白细胞激活蛋白（HP-NAP）能通过诱导人中性粒细胞和单核细胞产生IL-12 和IL-23，进而逆转Th1/Th2 漂移，被认为是增强Th1 型反应的免疫调节剂。HP-NAP的免疫学特性提示其可能是极具潜力的抗肿瘤治疗候选剂。基于此，课题主要对rMBP-NAP的抗肿瘤作用和作用机制进行了研究。结果显示，rMBP-NAP能够显著抑制肝癌H22，肉瘤S180及黑色素瘤B16的肿瘤生长，具有广泛的抗肿瘤作用,且rMBP-NAP能够抑制肿瘤新生血管生成，并促进肿瘤坏死。对rMBP-NAP的抗肿瘤作用机制进行研究发现，rMBP-NAP能够促进DCs的成熟，以IL-12/23轴依赖的方式逆转肿瘤Th1/Th2平衡，提升CD8+T细胞的数目及CTL的杀伤活性，发挥抗肿瘤作用。