Advanced solid tissue models of T-cell migration and activity

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GSK are committed to understanding fundamental biological processes and have a long running interest in immunology, especially relating to T-cell biology. The activities of cytotoxic T-cells are fundamental to development and in tissue degeneration and regeneration and are being studied extensively at GSK. It has however proved difficult to study cytotoxic T cell migration and activation in complex human 3D in vitro tissue culture models. In this project, we propose to adapt 3D multi-cellular human solid tissue models, recently established in the laboratory of Prof Balkwill at Queen Mary University of London, QMUL, to allow human T cell activities to be modelled, perturbed and measured in 3D. The ultimate aim will be to develop microfluidic methods and use 3D bio-printing techniques to build models where we can deliver genetically engineered T cells to malignant cells expressing relevant antigens in an appropriate tumour microenvironment.QMUL have expertise in tissue:extracellular matrix interactions and 3D modelling of complex tissues. Prof Balkwill's team has 'deconstructed' primary human gynaecological tissue from surgical samples as a readily available source of material, from which novel 3D models have been created by in vitro 'reconstruction'. The aim of the collaborative project is to incorporate T-cells, coupled with the development of assays for T-cell migration and activation, into the models. GSK have developed human in vitro model systems in which lentiviral transfected T cells have been engineered to express tool CAR or TCR molecules to recognise target cells in 2D cultures. Although GSK have considerable expertise in T-cell biology, they are not currently studying the role of ECM in T cell migration and activation. This project will allow us to bring together the immunological expertise of GSK with the tissue modelling expertise at QMUL to understand, in a physiologically relevant setting, the biological and biophysical variables that affect the capacity for T-cells to migrate within multicellular tissues.This collaboration between GSK and QMUL will ask firstly if we can integrate T-cells into the QMUL models to allow accurate recapitulation of T-cell infiltration and activation within complex tissues; and secondly, can we use these models to investigate mechanisms behind these processes?