Engineer Biomimetic Microfluidic Models to Investigate and Reprogram Tumor Associated Neutrophils for Cancer Therapy

设计仿生微流体模型来研究和重新编程肿瘤相关中性粒细胞以进行癌症治疗

基本信息

批准号：
10665743
负责人：
Xiaoping Bao
金额：
$ 34.55万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-15 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10665743
关键词：
3-Dimensional Address Animals Architecture Bioinformatics Biology Biomimetics Blood Blood - brain barrier anatomy Blood Vessels Cell Therapy Cells Chemotherapy and/or radiation Clinical Coculture Techniques Development Disease Effector Cell Engineering Evaluation Gelatinase B Gene Expression Genes Genetic Engineering Glioblastoma Goals Growth Hematopoietic stem cells Heterogeneity Human Human Engineering IL17 gene Immune Immunotherapy In Situ Infection Infiltration Inflammation Inflammatory Knowledge Life Longevity Lung Macrophage Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Malignant neoplasm of prostate Mature T-Lymphocyte Mediating MicroRNAs Microfluidic Microchips Microfluidics Microglia Modeling Morphology Mus Neoplasm Metastasis Neutropenia Neutrophil Infiltration Organoids Pathologic Patient Isolation Patients Phenotype Play Primary carcinoma of the liver cells Proteins Proteomics Publishing Radiation therapy Resistance Role Slice Solid Solid Neoplasm Specimen Testing Time Tissues Transforming Growth Factor beta Tumor Antigens Tumor Promotion Tumor stage Vascularization Xenograft procedure antitumor effect cancer cell cancer therapy cell type chemotherapy chimeric antigen receptor cytokine cytotoxicity engineered stem cells exosome experience genome editing improved in vivo induced pluripotent stem cell innovation insight interstitial mouse model neuro-oncology neutrophil novel novel strategies pre-clinical programs single-cell RNA sequencing targeted cancer therapy temozolomide therapeutic target therapy resistant tool transcriptome sequencing transplant model tumor tumor growth tumor heterogeneity tumor microenvironment tumor progression

项目摘要

Project Summary Neutrophils play critical roles during different stages of tumor development. In mice, systemic depletion of neutrophils results in decreased tumor growth in glioblastoma (GBM) and lung cancer, but promote tumor growth in pre-metastatic lung and other solid tumors, indicating their stage-specific and tissue-dependent functions in tumor progression. Neutrophils could also facilitate cancer cell resistance to chemotherapy, radiotherapy, and immunotherapy in different tumors by releasing various cytokines. Despite these preclinical and animal studies on tumor-associated neutrophils (TANs), a knowledge gap remains in our mechanistic understanding of how human neutrophils regulate cancer progression and therapeutic resistance in GBM, due to the short life and resistance to gene editing of neutrophils as well as technical hurdles in isolating stage-specific TANs. To address this gap, we propose to harness the power of microfluidics and human induced pluripotent stem cells (hiPSCs) to interrogate the diversity and plasticity of neutrophils in human GBM development. Elucidating the underlying mechanism will also enable the much-needed development and evaluation of neutrophil-targeted cancer therapy. Our central hypothesis here is that the microfluidic model will recapitulate the different stages of human tumor progression, providing a platform for phenotypic and mechanistic understanding of the roles of neutrophils in GBM development. To test this hypothesis, we will implement a novel interstitial tumor-microenvironment-on- chip (iT-MOC), and interrogate neutrophil-mediated tumor progression and therapeutic resistance at different GBM growth stages in Aim 1. Then in Aim 2, we will determine the morphology, polarization, life-span and antitumor cytotoxicity of GBM-infiltrating neutrophils. In Aim 3, we will reprogram tumor-associated neutrophils towards antitumor effector cells via genetic engineering of hiPSCs with chimeric antigen receptors (CARs) and microRNAs (miRNAs). This is a novel approach as human neutrophils cannot be genetically modified. Successful completion of these aims will offer an innovative platform to study the diversity and plasticity of TANs, and provide insights into reprograming them towards antitumor effector cells and the proof-of-concept for CAR-neutrophils in targeted cancer therapy.

项目概要中性粒细胞在肿瘤发展的不同阶段发挥着关键作用。在小鼠中，系统性耗竭中性粒细胞会导致胶质母细胞瘤 (GBM) 和肺癌的肿瘤生长减少，但会促进肿瘤生长在转移前的肺和其他实体瘤中，表明它们的分期特异性和组织依赖性功能肿瘤进展。中性粒细胞还可以促进癌细胞对化疗、放疗和化疗的抵抗力通过释放不同的细胞因子对不同的肿瘤进行免疫治疗。尽管有这些临床前和动物研究关于肿瘤相关中性粒细胞（TAN），我们对如何机制的理解仍然存在知识差距由于寿命短，人类中性粒细胞可调节 GBM 的癌症进展和治疗耐药性对中性粒细胞基因编辑的抵抗以及分离特定阶段 TAN 的技术障碍。致地址为了弥补这一差距，我们建议利用微流体和人类诱导多能干细胞（hiPSC）的力量探究人类 GBM 发育中中性粒细胞的多样性和可塑性。阐明底层该机制还将促进急需的中性粒细胞靶向癌症治疗的开发和评估。我们的中心假设是微流体模型将重现人类肿瘤的不同阶段进展，为了解中性粒细胞在表型和机制上的作用提供了一个平台 GBM 的发展。为了检验这一假设，我们将实施一种新型的间质性肿瘤微环境- 芯片（iT-MOC），并在不同的条件下询问中性粒细胞介导的肿瘤进展和治疗耐药性目标 1 中的 GBM 生长阶段。然后在目标 2 中，我们将确定形态、极化、寿命和 GBM 浸润性中性粒细胞的抗肿瘤细胞毒性。在目标 3 中，我们将重新编程肿瘤相关中性粒细胞通过嵌合抗原受体（CAR）对 hiPSC 进行基因工程，产生抗肿瘤效应细胞微小RNA（miRNA）。这是一种新颖的方法，因为人类中性粒细胞无法进行基因改造。成功的这些目标的完成将为研究 TAN 的多样性和可塑性提供一个创新平台，并提供将它们重新编程为抗肿瘤效应细胞的见解以及 CAR-中性粒细胞的概念验证靶向癌症治疗。