Imaging T-cell triggering on tumour cells

Lead Research Organisation: UNIVERSITY OF CAMBRIDGE
Department Name: Chemistry

Abstract

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.

Publications

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Description We have developed a model cell surface to study triggering of T cells based on a lipid bilayer which is more realistic than models used t date. We have studied triggering of T cells on a cancer cell and can follow the early events that occur and start to understand how the cancer cells escape the immune response. In particular this work highlighted the role of the cell glyocalyx in allowing cells to escape the immune response.
Exploitation Route Our results present a detailed picture of the early events of a Tcell recognising a cancer cell and mounting an immune response showing that this proceeds by a model that we developed, the kinetic segregation model where triggering is based on excluding large phosphatases from the close contact between the T cell and cancer cell. We also found this triggering of the T cell is much slower than on our bilayers and this seems to be due to the thicker glycocalyx on the cancer cell surface. While it is known that cancer cells have thicker glycocalces it is a surprise that it has such a profound effect and explains why cancer cells are challening to treat by immunotherapy. It suggests that reducing the glycocalyx is a good strategy for improved therapies.
Sectors Pharmaceuticals and Medical Biotechnology