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Role of extracellular matrix remodeling on high-grade serous ovarian carcinoma immune evasion

细胞外基质重塑在高级别浆液性卵巢癌免疫逃避中的作用

基本信息

批准号：
10573243
负责人：
Pilar de la Puente
金额：
$ 19.01万
依托单位：
SANFORD RESEARCH/USD
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：
2022-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10573243
关键词：
3-Dimensional Action Research Address Affect Animals Antitumor Response Attenuated Biochemical Biological Biological Assay Cell Communication Cells Data Development Drug resistance Engineering Exclusion Experimental Models Extracellular Matrix Goals Hypoxia Immune Immune Evasion Immune response Immunologic Surveillance Immunosuppression Immunotherapy Impairment Incidence Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of ovary Modeling Nature Ovarian Serous Adenocarcinoma Oxygen Patients Positioning Attribute Pre-Clinical Model Recreation Research Methodology Research Priority Role Sampling System T-Lymphocyte Testing Time Tissues Tumor Escape Tumor Tissue Tumor-Infiltrating Lymphocytes Woman Work cancer cell cancer subtypes cell behavior cell dimension cost experimental study immune cell infiltrate immune checkpoint immune checkpoint blockade immune function improved outcome insight mechanical properties meetings new technology novel novel strategies ovarian neoplasm prognostic indicator reconstruction response three-dimensional modeling tissue culture tumor tumor hypoxia tumor microenvironment tumor progression

项目摘要

The broad goal of the proposed work is to understand how the hypoxia-induced extracellular matrix (ECM) remodeling in ovarian cancer affects immune evasion. Understanding this concept would have a broad impact on identifying effective immunotherapies for ovarian cancer, a particularly deadly form of cancer in women. The ECM not only provides structural and biochemical support to tumor tissue, but also the ECM undergoes remodeling which alters the composition and mechanical properties of the tumor microenvironment, directly influencing immune evasion mechanisms. With this in mind, it has been established that hypoxia can influence tumor immunosuppression and this inadequate tissue oxygen, or hypoxia, promotes ECM remodeling. However, little is known about the role of the hypoxia-induced ECM in immune evasion and response to immunotherapy in ovarian cancer. Unfortunately, there is a scarcity of preclinical models providing recapitulation of the hypoxia-induced ECM remodeling of ovarian tumors. Thus, new technologies that allow the study of the hypoxia-induced ECM remodeling and its impact on immune evasion are crucially required. In studies leading to this application, we developed a patient-derived 3D tissue culture system capable of recapitulating the hypoxia-induced ECM and tumor-immune interactions. Specifically, we will utilize engineering approaches and patient-derived samples in order to assess the effect of the hypoxia-induced ECM remodeling on the tumor-immune cycle and further validate new treatments to overcome immune evasion. Successful completion of the proposed work will allow us to investigate the role of the hypoxia-induced ECM remodeling on cancer immune evasion, to identify how tumors escape immune surveillance, and to ascertain novel strategies to re-sensitize cancer cells to immune cells reducing tumor immune evasion in a precision-based manner.

这项工作的主要目标是了解缺氧诱导的细胞外基质（ECM）卵巢癌中的重塑影响免疫逃避。理解这一概念将产生广泛的影响为卵巢癌找到有效的免疫疗法，这是一种特别致命的女性癌症。的 ECM不仅为肿瘤组织提供结构和生物化学支持，而且ECM还经历重塑，直接改变肿瘤微环境的组成和机械特性影响免疫逃避机制。考虑到这一点，已经确定缺氧可以影响肿瘤免疫抑制和这种不足的组织氧或缺氧促进ECM重塑。然而，在这方面，关于低氧诱导的ECM在免疫逃避和对免疫治疗的应答中的作用知之甚少在卵巢癌中。不幸的是，缺乏临床前模型来重现缺氧诱导的ECM，卵巢肿瘤的重塑因此，允许研究缺氧诱导的ECM的新技术重塑及其对免疫逃避的影响是至关重要的。在导致该应用的研究中，我们开发了一种能够重现缺氧诱导的ECM的患者来源的3D组织培养系统，肿瘤免疫相互作用。具体来说，我们将利用工程方法和患者来源的样本，为了评估缺氧诱导的ECM重塑对肿瘤免疫周期的影响，验证克服免疫逃避的新疗法。成功完成拟议工作将使我们研究了缺氧诱导的ECM重塑在癌症免疫逃避中的作用，以确定如何肿瘤逃避免疫监视，并确定新的策略，使癌细胞对免疫系统重新敏感。细胞以基于精确度的方式减少肿瘤免疫逃避。