Imaging T-cell triggering on tumour cells

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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.