Research Testbed 1

研究试验台1

• 批准号: 10538593
• 负责人: Paolo Provenzano
• 金额: $ 39.9万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-09 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10538593
• 关键词: Architecture; Automobile Driving; Behavior; Biophysical Process; Cancer Prognosis; Cell physiology; Cells; Chemicals; Clinical; Combined Modality Therapy; Complex; Coupled; Cues; Cytotoxic T-Lymphocytes; Desmoplastic; Disease; Disease Outcome; Engineering; Environment; Experimental Models; Extracellular Matrix; Fingerprint; Generations; Genome engineering; Goals; Halofuginone; Image; Immune; Immunosuppression; Immunotherapy; In Vitro; Infiltration; Infusion procedures; KPC model; Link; Machine Learning; Malignant Epithelial Cell; Malignant Neoplasms; Maps; Mechanics; Mediating; Microtubules; Molecular; Multiplexed Ion Beam Imaging; Myelogenous; Myeloid-derived suppressor cells; Optics; Pancreatic Ductal Adenocarcinoma; Pancreatic carcinoma; Phenotype; Population; Radiation therapy; Research; Resistance; Resolution; Role; Sampling; Signal Transduction; Slice; Solid Neoplasm; Spectrum Analysis; Speed; Structure; Survival Rate; System; T cell infiltration; T cell therapy; T-Lymphocyte; Testing; Tissues; Treatment Efficacy; Tumor Volume; Tumor-associated macrophages; Tumor-infiltrating immune cells; cancer imaging; cell behavior; cell motility; cell transformation; cellular engineering; chemical reduction; cohort; design; engineered T cells; experimental study; fluorescence lifetime imaging; genetically modified cells; imaging study; immune checkpoint blockade; improved; in vivo; intravital imaging; mathematical model; migration; multi-photon; multimodality; multiparametric imaging; novel; optical imaging; physical property; pre-clinical; response; rho; second harmonic; success; targeted treatment; technology development; tumor; tumor microenvironment; tumor-immune system interactions

Pancreatic ductal adenocarcinoma is an extremely lethal disease with the lowest 1-year and 5-year survival rates of any cancer. This is due, in part, to the extremely metastatic behavior of pancreas carcinoma cells and their extreme resistance to both chemical and radiotherapies. Importantly, we now know that a strong, but nevertheless unique, fibrotic and immunosuppressive stromal response is present in PDA. This intense fibroinflammatory, or desmoplastic, response is essentially pathognomonic for PDA and limits infiltration of anti-tumor immune cells and also their ability to move throughout and sample the tumor volume. Indeed, immunotherapies with immune checkpoint blockade or infusion of genetically modified cells are producing remarkable clinical responses in other advanced malignancies, but to date, success has been much more limited in PDA. However, focused preclinical strategies to disrupt the stroma or specifically engineer T cell therapies have shown promise in PDA. Thus, understanding the physical and molecular basis for native and engineered T cell infiltration and defining strategies to further enhance their infiltration, migration throughout tumor masses, and function in cancer will inform cell engineering strategies for improved treatment. Here, we test a number of focused hypotheses using advanced optical imaging with state-of-the-art in vivo systems, engineered environments, genome engineering, and mathematical modeling to better define how T cells successfully move through some environments but are impeded by others. We hypothesize that by defining design criteria that can be employed to help engineer T cells to move throughout tumor volumes we can profoundly improve therapeutic efficacy and employ combinations therapies to improve disease outcomes. Therefore, here, through advanced imaging and quantitative analysis we will dissect physical and molecular mechanisms governing migration and function of both native and engineered T cells. We will define the roles of both matrix architecture and immunosuppressive cells populations, and the links between the two. This information will provide tookits to engineer T cells that most effectively move throughout the entire tumor mass. Our goals are aligned with the TECH unit, where we will perform iterations between experiments, analysis, and technology development, and RTB-2 to define approaches to improve therapy in poor prognosis cancers. Collectively, we seek to elucidate fundamental mechanisms of immune cell migration and define approaches to transform cell engineering therapies to eradicate cancer.

胰腺导管腺癌是一种极其致命的疾病，其1年和5年生存率最低。 任何癌症的比率。这在一定程度上是由于胰腺癌细胞的极端转移行为和 他们对化学疗法和放射疗法都有极端的抵抗力。重要的是，我们现在知道，一个强大的，但 然而，PDA存在独特的、纤维化的和免疫抑制的间质反应。如此激烈 纤维炎性或促结缔组织增生性反应本质上是PDA的病因学反应，并限制了 抗肿瘤免疫细胞以及它们在整个肿瘤体积中移动和取样的能力。的确， 免疫检查点阻断或转基因细胞输注的免疫疗法正在产生 在其他晚期恶性肿瘤中有显著的临床反应，但到目前为止，成功的更多 仅限于掌上电脑。然而，专注于临床前策略来破坏基质或专门设计T细胞 治疗方法在PDA方面显示出了希望。因此，了解自然和生物的物理和分子基础 设计T细胞渗透和定义策略，以进一步加强其渗透和迁移 肿瘤的质量和癌症中的功能将为改进治疗的细胞工程策略提供信息。在这里，我们 使用先进的光学成像技术和最先进的活体系统测试一系列聚焦假说， 工程环境、基因组工程和数学建模，以更好地定义T细胞如何 成功地通过了一些环境，但受到其他环境的阻碍。我们假设通过定义 可以用来帮助设计T细胞在肿瘤体积中移动的设计标准 深刻提高治疗效果，采用综合疗法改善疾病结局。 因此，在这里，我们将通过先进的成像和定量分析来解剖物理和分子 控制天然T细胞和工程T细胞迁移和功能的机制。我们将定义以下角色 包括基质结构和免疫抑制细胞群，以及两者之间的联系。这 信息将为设计最有效地在整个肿瘤中移动的T细胞提供工具。 我们的目标是与技术单位保持一致，在那里我们将在实验、分析和 技术发展，以及RTB-2，以确定改善预后不良癌症治疗的方法。 总而言之，我们试图阐明免疫细胞迁移的基本机制，并定义 改变细胞工程疗法以根除癌症。