Advanced solid tissue models of T-cell migration and activity
Lead Research Organisation:
Queen Mary University of London
Department Name: Barts Cancer Institute
Abstract
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?
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?
People |
ORCID iD |
Joash Joy (Student) |
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
BB/R505298/1 | 02/10/2017 | 25/03/2022 | |||
1959727 | Studentship | BB/R505298/1 | 01/10/2017 | 31/03/2022 | Joash Joy |
Description | The impaired death receptor signaling in ovarian cancer cell lines can prevent chimeric antigen receptor (CAR)-T cell-directed killing. CAR-T cell activity can be modulated both positively and negatively by fibroblasts. In spheroid cultures with cancer cell lines and fibroblasts, chemokine C-C motif ligand 2 (CCL2) secreted by fibroblasts activated CAR-T cells to induce cytotoxicity against cancer cells. However, in slightly more complex 3-dimensional models in which cancer cells and fibroblasts were cultured in collagen gels, the extracellular matrix (ECM) produced primarily by fibroblasts prevented CAR-T cell infiltration and cytotoxicity. Targeting the ECM production in these models enhanced CAR-T cell activity. |
Exploitation Route | CAR-T cell activity can be tested in more complex and more relevant 3D in vitro multicellular human cancer models. 3D model models can be used to investigate strategies to improve CAR-T cell therapy in solid tumours. |
Sectors | Pharmaceuticals and Medical Biotechnology |