Research Testbed 1

研究试验台1

• 批准号: 10374453
• 负责人: Paolo Provenzano
• 金额: $ 35.17万
• 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/10374453
• 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; 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 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; 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; 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致命的疾病，其1年和5年生存率最低 任何癌症的发病率。这部分是由于胰腺癌细胞的极端转移行为， 他们对化学和放射疗法的极端抵抗力。重要的是，我们现在知道，一个强大的，但 然而，PDA中存在独特的纤维化和免疫抑制基质反应。这种强烈 纤维炎性反应或促结缔组织增生反应是PDA的主要特征， 抗肿瘤免疫细胞以及它们在肿瘤体积中移动和取样的能力。的确， 具有免疫检查点阻断或输注遗传修饰细胞的免疫疗法正在产生 在其他晚期恶性肿瘤中的临床反应显着，但迄今为止， 仅限于PDA。然而，集中的临床前策略破坏基质或特异性工程化T细胞， 治疗PDA的方法已显示出前景。因此，了解天然和 工程化T细胞浸润和定义策略，以进一步增强其浸润，迁移， 肿瘤质量和癌症中的功能将为改善治疗的细胞工程策略提供信息。这里我们 使用先进的光学成像技术和最先进的体内系统来测试一些重点假设， 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 成功地通过某些环境，但受到其他环境的阻碍。我们假设通过定义 设计标准，可以用来帮助工程师T细胞移动整个肿瘤体积，我们可以 深刻地提高治疗效果，并采用组合疗法来改善疾病结果。 因此，在这里，通过先进的成像和定量分析，我们将解剖物理和分子 调节天然和工程化T细胞的迁移和功能的机制。我们将定义 基质结构和免疫抑制细胞群，以及两者之间的联系。这 这些信息将为设计T细胞提供工具，使其最有效地在整个肿瘤块中移动。 我们的目标与TECH单元一致，在TECH单元中，我们将在实验、分析和 技术开发和RTB-2，以确定改善预后不良癌症治疗的方法。 总的来说，我们试图阐明免疫细胞迁移的基本机制，并确定方法， 改造细胞工程疗法以根除癌症。