ARTificial Tumour Immune MicroEnvironment for structured profiling of cancer immune adaptation

在ART-TIME的框架内，我将为人类胰腺癌类器官开发一个人工肿瘤免疫微环境（ART-TIME），赋予肿瘤免疫适应的结构化和理性分析。免疫细胞是免疫微环境的决定性要素，因此，将通过从其单分子构建块自下而上的组装，将其重新创建为合成细胞。可编程合成细胞将被引入肿瘤类器官，作为逼真的白细胞模拟物，呈现免疫效应功能。通过这种方法，分子定义的免疫环境将首次在肿瘤模型中被创造出来。基于成像的多参数筛选将评估类器官发育以及免疫治疗反应作为ART-TIME配置的功能。这一策略将把时间结构与癌症免疫适应和逃避联系起来，以定量描述治疗耐药性。因此，ART-TIME致力于消除肿瘤免疫微环境的动态复杂性，以实现合理的解剖。此外，ART-TIME将为体现活细胞基本特征的混合生物材料的组装提供概念。在牛津大学由Michael Dustin教授主持的这项奖学金中，我将利用可编程人造材料贡献肿瘤免疫学的基础知识。我的地理过渡到一个具有临床导向基础设施的研究环境，将大大扩展我的科学视野，完善我的学术形象。得益于我在自下而上合成生物学方面的专业知识和宿主在免疫学方面的高质量研究之间的协同作用，这个跨学科项目将为合成细胞开辟广阔的前景，通过在生物和非生物世界之间的消失边界上创造混合材料来操纵组织模式-这是我未来研究生涯的重点。

Within the framework of ART-TIME, I will develop an artificial tumour immune microenvironment (ART-TIME) for human pancreatic cancer organoids empowering structured and rational analysis of tumour immune adaptations. Immune cells, the defining elements of an immune microenvironment, will thus be recreated as synthetic cells by bottom-up assembly from their single molecular building blocks. The programmable synthetic cells will be introduced into tumour organoids to function as lifelike leukocyte mimics presenting immune effector functions. By this, a molecularly defined immune environment will be created inside tumour models for the first time. Imaging-based multi-parametric screenings will assess organoid development as well as immunotherapy response as a function of the ART-TIME configuration. This strategy will link TIME architectures to cancer immune adaptation and evasion for quantitative description of therapy resistance. Therefore, ART-TIME strives to de-convolute the dynamic complexity of the tumour immune microenvironment towards a rational dissection. Moreover, ART-TIME will contribute concepts for the assembly of hybrid biomaterials that embody essential features of living cells. Within this fellowship, hosted at the University of Oxford by Prof. Michael Dustin, I will contribute fundamental knowledge on tumour immunology using programmable man-made materials. My geographic transition into a research environment with clinically oriented infrastructure will significantly expand my scientific horizon and refine my academic profile. Greatly profiting from the synergy between my expertise on bottom-up synthetic biology and the host's highquality research on immunology, this interdisciplinary project will open up broad perspectives for synthetic cells capable of manipulating tissue patterns by creating hybrid materials at the vanishing boarders between the living and non-living world - the envisioned focus of my subsequent research career.