Research Testbed 1

研究试验台1

基本信息

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
项目类别：
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

项目摘要

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，1年和5年生存率最低任何癌症的发生率。这部分是由于胰腺癌细胞的极端转移行为和它们对化学疗法和放射疗法具有极强的抵抗力。重要的是，我们现在知道，一个强大但然而，PDA 中存在独特的纤维化和免疫抑制基质反应。这种激烈的纤维炎症或促纤维增生反应本质上是 PDA 的特有特征，并限制了 PDA 的浸润。抗肿瘤免疫细胞及其在肿瘤体积中移动和采样的能力。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取得了显着的临床反应，但迄今为止，成功的程度要大得多仅限于 PDA。然而，重点临床前策略是破坏基质或专门改造 T 细胞疗法在 PDA 中显示出前景。因此，了解天然和分子的物理和分子基础工程化 T 细胞渗透并定义策略以进一步增强其渗透、迁移肿瘤块和癌症功能将为改善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和最先进的体内系统测试许多集中的假设，工程环境、基因组工程和数学建模，以更好地定义 T 细胞如何成功地穿过某些环境，但受到其他环境的阻碍。我们假设通过定义设计可用于帮助设计 T 细胞在整个肿瘤体积中移动的标准，我们可以深刻提高治疗效果并采用联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，我们将剖析物理和分子控制天然 T 细胞和工程 T 细胞的迁移和功能的机制。我们将定义角色基质结构和免疫抑制细胞群，以及两者之间的联系。这信息将提供工具来设计T细胞，使其最有效地在整个肿瘤块中移动。我们的目标与技术部门保持一致，我们将在实验、分析和结果之间进行迭代技术开发和 RTB-2 来定义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定义免疫细胞迁移的方法转变细胞工程疗法以根除癌症。