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Research Testbed 1

研究试验台1

基本信息

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
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/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

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具致命性的疾病，其1年和5年生存率最低