Advanced solid tissue models of T-cell migration and activity

GSK致力于了解基本的生物学过程，并对免疫学，特别是与t细胞生物学相关的免疫学有着长期的兴趣。细胞毒性t细胞的活性是发育、组织退化和再生的基础，GSK正在对其进行广泛的研究。然而，在复杂的人体3D体外组织培养模型中研究细胞毒性T细胞的迁移和激活是困难的。在这个项目中，我们建议采用最近在伦敦玛丽女王大学Balkwill教授实验室建立的3D多细胞人体实体组织模型，以允许在3D中模拟，干扰和测量人体T细胞活动。最终目标将是开发微流体方法，并使用3D生物打印技术来构建模型，我们可以在适当的肿瘤微环境中将基因工程T细胞传递给表达相关抗原的恶性细胞。QMUL在组织方面拥有专业知识：细胞外基质相互作用和复杂组织的3D建模。巴尔克威尔教授的团队已经从手术样本中“解构”了原始的人类妇科组织，作为一种现成的材料来源，通过体外“重建”，他们已经创建了新的3D模型。该合作项目的目的是将t细胞与t细胞迁移和激活的检测方法结合到模型中。GSK已经开发出人体体外模型系统，其中慢病毒转染的T细胞已被改造成表达工具CAR或TCR分子，以识别2D培养中的靶细胞。虽然GSK在T细胞生物学方面有相当的专业知识，但他们目前还没有研究ECM在T细胞迁移和激活中的作用。该项目将使我们能够将GSK的免疫学专业知识与QMUL的组织建模专业知识结合起来，在生理学相关的环境中了解影响t细胞在多细胞组织中迁移能力的生物和生物物理变量。GSK和QMUL之间的合作将首先询问我们是否可以将t细胞整合到QMUL模型中，以便准确再现复杂组织中t细胞的浸润和激活；其次，我们可以用这些模型来研究这些过程背后的机制吗？

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?