越来越多的证据表明在肿瘤治疗过程中溶瘤病毒诱发的抗肿瘤细胞和病毒蛋白的T细胞免疫反应发挥着关键作用。解析机体对肿瘤细胞和溶瘤病毒的T细胞免疫反应将为提高溶肿瘤病毒疗效开辟新的方法。最近发现，瘤内注射肿瘤靶向复制型溶瘤痘苗病毒（VV）能产生一群特殊的T细胞亚群，这类T细胞有双T细胞受体，能同时与肿瘤相关抗原和病毒蛋白反应。更重要的是，用VV多肽激活用痘苗病毒治疗过的动物脾细胞能有效、特异地杀伤肿瘤细胞。本课题将通过一系列体外，间接体外和体内实验来评估溶肿瘤痘苗病毒在治疗肿瘤过程中所产生的双受体T细胞的功能作用；研究识别痘苗病毒B8R表位及肿瘤相关抗原的双受体T细胞的多样性；筛选能诱导产生双受体T细胞的痘苗病毒蛋白表位; 验证痘苗病毒载体表达的特殊抗原能否引发双受体T细胞；从而探讨一种新的靶向双受体T细胞的肿瘤治疗方法。本课题将为增强痘苗病毒载体介导的疫苗和溶肿瘤病毒的疗效提供新策略。

Accumulating evidence suggest that oncolytic virus-induced host T cell immunity plays an important role in the anti-tumour efficacy.Dissection of T cell responses against tumour cells and oncolytic virus will open new avenues to further potentiate the efficacy of oncolytic virus. Encouraging evidence in support of this application shows that intratumoral injection of Tumour-targeted replicating oncolytic vaccinia virus (TOVV) could result in a particular population of T cells: dual Cell receptor T cells specifically reacting with both tumour-associated antigens and viral proteins. Most strikingly, in vitro, the re-activated spleen cells with VV-specific peptides could effectively and specifically kill tumour cells. In this proposed project we will perform a series of in vitro, ex vivo and in vivo experiments and achieve the following five objectives: Evaluation of dual TCR T cell function on the efficacy of replicating VV for cancer treatment; Evaluation of the diversity of the dual TCR T cells specifically recognizing both VV B8R epitopes and TAAs; Screening of the epitopes of VV proteins that produce these dual TCR T cells; Evaluation of whether a particular antigen delivered by VV vector can induce dual TCR T cells against the antigen and VV and development of a new therapeutic cancer therapeutic regime by targeting dual TCR T cells. This project will provide a novel strategy to improve the efficacy of VV-based vaccination and cancer therapy.