HSV1减毒株M6在溶瘤治疗中的免疫模式及其机理研究

抗程序性死亡受体1（PD-1）类单克隆抗体作为以免疫模式调控为中心的抗肿瘤药物，已在临床治疗中显示出其重要的潜力。基于这一受体功能阻断而实现肿瘤细胞杀伤效应的策略，进一步提示了配体-受体相互作用概念的拓展对肿瘤治疗原理的补充。单纯疱疹病毒（HSV）作为一个具有多个表面糖蛋白，并能够与不同细胞表面受体结合的特殊病毒，能够为受体-配体结合以在肿瘤免疫调控中发挥作用提供空间。我们在具有明确减毒特性的HSV1毒株的基础上，利用PD-1的拮抗物PD-1显性负性受体(DNR)替换了HSV1表面糖蛋白gD中与免疫细胞结合且具有免疫抑制作用的HVEM分子结合域，构建了减毒株M4。本研究拟对M4毒株中与免疫逃逸密切相关的基因进一步予以缺失突变，获得突变株M6；随后对M6通过调节免疫杀伤效应，并可借助PD-1DNR进入肿瘤细胞发挥溶瘤作用的可能机理进行深入的探讨，为研究免疫调控-溶瘤作用的技术可能提供资料。

The anti-programmed cell death receptor 1 (PD-1) monoclonal antibodies have shown favorable clinical activities as anti-tumor agents regarding the regulation of immune response. The strategy of tumor immunotherapy by blocking PD-1 further suggests that interactions between ligands and receptors are likely to possess a vast potential in tumor treatment. Being a specific virus that contains multiple envelope glycoproteins to bind to various cell surface receptors, herpes simplex virus (HSV) can act as a vector appreciable for targeted delivery of drugs to improve tumor therapeutic index. Based on the establishment of a HSV1 strain with well-defined attenuate phenotype, we have constructed a mutant strain M4, in which the PD-1 dominant negative receptor (PDR), a PD-1 antagonist, was designed to replace the HVEM molecule-binding domain in glycoprotein D. This study is to construct a mutant strain M6 via modifying the genes associated with immune escape. More importantly, by exploring the role of PD-1 DNR in the process of M6 locating into tumor cells, our aim is to investigate the possible mechanism of the oncolytic effect of strain M6. This study may provide foundation for the application of the immunomodulatory-oncolytic technique in tumor therapy.