Advanced solid tissue models of T-cell migration and activity

葛兰素史克致力于了解基本的生物过程，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细胞的活动是发育、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组织培养模型中，研究细胞毒T细胞的迁移和激活已被证明是困难的。在这个项目中，我们建议采用最近在伦敦玛丽女王大学巴尔威尔教授的实验室建立的3D多细胞人体实体组织模型，以允许在3D中模拟、干扰和测量人类T细胞的活动。最终目标将是开发微流控方法并使用3D生物打印技术建立模型，在此模型中，我们可以将基因工程T细胞输送到在适当的肿瘤微环境中表达相关抗原的恶性肿瘤细胞。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’出了原始的人类妇科组织，作为一种容易获得的材料来源，通过体外‘重建’，已经从这些组织中创建了新的3D模型。该合作项目的目的是将T细胞与T细胞迁移和激活检测的开发结合到模型中。葛兰素史克已经开发了人类体外模型系统，其中慢病毒感染的T细胞被设计为表达工具CAR或TCR分子，以识别2D培养中的目标细胞。尽管葛兰素史克在T细胞生物学方面拥有相当多的专业知识，但他们目前还没有研究细胞外基质在T细胞迁移和激活中的作用。这个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，以便准确地概括T细胞在复杂组织中的渗透和激活；其次，我们是否可以使用这些模型来研究这些过程背后的机制？

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?