Imaging T-cell triggering on tumour cells

癌症是全球第二大死亡原因，为了开发更有效的治疗方法，我们仍然迫切需要更好地了解免疫系统对癌症的反应。我们建议利用Klenerman实验室开发的基于单分子荧光的方法，研究t细胞受体（TCR）、嵌合抗原受体（CAR） Jurkat和原代t细胞与表达黑色素瘤抗原的U-2骨肉瘤肿瘤细胞形成的早期接触。我们将成像的关键信号分子，最初的接触形式，然后导致免疫受体触发。特别是，我们将测试排除大型磷酸酶是否驱动信号传导过程，因为这可能允许我们通过改变所用抗体的尺寸来增加免疫反应。通过比较双特异性t细胞接合物（BiTEs）和ImmTAXsTM的作用，我们将确定这些t细胞重定向疗法的分子机制。抗PD-1抗体（nivolumab及其类似物）将在t细胞/肿瘤密切接触者中进行临床测试，以取代有毒的PD-1/CTLA-4联合治疗癌症。比较密切接触的t细胞/肿瘤相互作用，我们希望确定免疫受体触发的一般机制，使我们能够识别和商业化最合适的纳武单抗类似物，以改善治疗和早期疾病诊断。我们的项目将根据可交付成果，里程碑和甘特图实施。结果将通过高影响力的出版物/会议传播，并在欧盟委员会和剑桥大学的帮助下在不同的目标受众之间进行交流。这项尖端的科学提案符合欧盟4health计划，并将在一个领先的多学科研究小组中完成。研究人员和主办实验室之间的双向知识转移将有助于项目的成功，以及研究人员的独立职业生涯。

Cancer is the second leading cause of worldwide death and there is still an urgent need to better understand how the immune system responds to cancer in order to develop more effective treatments. We propose to exploit single molecule fluorescence-based methods, developed in the Klenerman laboratory, to study the early contacts formed by T-cell receptor (TCR), chimeric antigen receptor (CAR) Jurkat and primary T-cells with the U-2 osteosarcoma tumour cells, expressing a melanoma antigen. We will image the key signaling molecules as initial contacts form and then lead to immune receptor triggering. In particular, we will test if exclusion of large phosphatases drives the signaling process since this may allow us to increase the immune response by altering the dimensions of the antibodies used. By comparing the effects of bispecific T-cell engagers (BiTEs) and ImmTAXsTM, we will determine the molecular mechanism of these T-cell redirection therapies. Anti-PD-1 antibodies (nivolumab and its analogs) will be clinically tested at T-cell/tumour close-contacts to replace the toxic PD-1/CTLA-4 combination therapy for cancer. Comparing T-cell/tumour interactions at close contacts, we hope to determine the general mechanism of immunoreceptor triggering, allowing us to identify and commercialize the most suitable nivolumab analogs for the betterment of treatment as well as early disease diagnosis. Our project will be implemented according to deliverables, milestones and Gantt chart. The results will be disseminated through high impact publications/conferences and communicated among different target audiences with the help of EU commission and the University of Cambridge. This cutting-edge scientific proposal is in line with the EU4Health programme and will be completed in a leading multidisciplinary research group. The two-way knowledge transfer between researcher and host lab will facilitate the success of the project as well as researcher's independent career.