Mechanisms of Exosome Driven Immunoregulation of Cancer Progression

外泌体驱动的癌症进展免疫调节机制

基本信息

批准号：
10671960
负责人：
Robert Blelloch
金额：
$ 4万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-23 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10671960
关键词：
Address Antibodies Basic Science Beds Biotin Blocking Antibodies Bypass Cancer Model Cell Communication Cell Line Cell physiology Cell surface Cells Clinical Sciences Data Disease remission Distal Distant Fostering Goals Health Human Immune Immune checkpoint inhibitor Immune system Immunity Immunologics Immunosuppression Immunotherapy In Vitro Injections Integral Membrane Protein Knowledge Label Lead Ligands Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Malignant neoplasm of pancreas Malignant neoplasm of prostate Manipulative Therapies Mass Spectrum Analysis Membrane Proteins Memory Microscopy Mission Modeling Monoubiquitination Mus PD-L1 blockade Pathway interactions Patients Proteins Proteomics Public Health Renal carcinoma Research Research Personnel Resistance Role Sampling Site Sorting - Cell Movement Structure Surface T-Cell Activation T-Lymphocyte Testing Therapeutic Therapeutic antibodies Translational Research Tumor Immunity Tumor-Derived United States National Institutes of Health Vaccines Variant Vision anti-PD-1 anti-PD-L1 anti-PD-L1 antibodies anti-PD-L1 therapy anti-tumor immune response antigen-specific T cells base cancer care cancer cell cancer therapy cancer type cell type checkpoint therapy differential expression draining lymph node exosome experimental study immune checkpoint immunoregulation improved in vitro Model in vivo Model insight melanoma mutant neoplastic cell novel strategies novel therapeutic intervention personalized cancer therapy programmed cell death ligand 1 programmed cell death protein 1 protein function public health relevance receptor refractory cancer response success therapy resistant tumor tumor progression

项目摘要

PROJECT ABSTRACT: Antibodies against the immune checkpoint proteins PD-L1 and PD-1 have revolutionized cancer therapeutics resulting in durable remissions in many patients previous considered incurable. However, a majority of patients remain resistant and cancer types can vary greatly in their response rates. Thus, there is an urgent need to understand the variation in response in order to improve cancer care. This proposal brings together a team of investigators with complementary expertise in basic, translational, and clinical science who share the long-term goal of finding novel approaches to categorize and personalize cancer treatments. Recent results from the investigators suggest a major role for the packaging of immune checkpoint proteins in exosomes underlying the variation in responses to immune checkpoint inhibitors among patients. Specifically, varying amounts of PD-L1 can be trafficked to exosomes, which in turn can act at a distance to suppress anti-tumor T cell function, enabling tumor progression, even in models resistant to anti-PD-L1 treatments. The objective of this proposal is to build on these findings by focusing on the mechanism of exosomal PD-L1 packaging, action, and resistance to therapeutic antibodies. In particular, the proposal will test the overall hypothesis that tumor cells can selectively package PD-L1 into exosomes that suppress T cell priming at distal sights in a fashion that is distinct from the cell-cell interactions of PD-L1 and PD-1 normally seen in the tumor bed. The hypothesis is premised on extensive preliminary data using in vitro and in vivo models showing that the relative fraction of PD-L1 packaged in exosomes versus retained in cells varies between cell lines, that suppression of exosomal PD-L1 can result in long-term systemic anti-tumor immunity, and that exosomal PD-L1 is resistant to anti-PD-L1 antibodies. To test the overall hypothesis, the following aims are proposed: 1) Uncover mechanisms underlying the selective packaging of PD-L1 into exosomes, 2) Evaluate the mechanistic basis of exosomal PD-L1’s impact on systemic immunity, 3) Dissect how exosomal PD-L1 interacts with and regulates its target cells. In aim 1, structure/function and proteomic approaches are proposed to identify the regulators of PD-L1 packaging into exosomes. Furthermore, associations between expression of these factors and resistance to therapy will be evaluated using primary patient samples. In aim 2, mouse-based immunological approaches and patient samples will be used to determine where in the immune axis exosomal PD-L1 functions. Uncovered insights will then be used to develop a novel therapeutic approach to enhance the anti-tumor immune response. In aim 3, microscopy and functional studies in in vitro models along with association studies with patient samples will be used to determine how exosomal PD-L1 interacts with its target cells potentially explaining its resistance to antibodies. The proposal is highly significant in that it is expected to provide new fundamental knowledge that can be used to identify and treat the large fraction of patients resistant to current immune therapies. While this proposal focuses on a subset of cancer models with a particular emphasis on prostate cancer, the paradigms uncovered are expected to be relevant across most if not all tumor types.

项目摘要：针对免疫切除蛋白PD-L1和PD-1的抗体已彻底改变了癌症治疗导致许多先前被认为无法治愈的患者持续恢复。但是，大多数患者保持耐药性，癌症类型的反应率可能差异很大。那迫切需要了解以改善癌症护理的响应差异。该提议汇集了一个团队具有基础，翻译和临床科学专业知识的研究人员，他们共享长期的寻找新颖的方法来对癌症治疗进行分类和个性化。来自研究人员建议在外泌体中包装免疫检查点蛋白包装的主要作用患者对免疫切除剂抑制剂的反应变化。具体而言，大量的PD-L1数量可以将外泌体运输到外泌体，而外泌体可以在距离抑制抗肿瘤T细胞功能的距离上起作用，从而使肿瘤进展，即使在抗抗PD-L1处理的模型中也是如此。该提议的目的是建立在这些发现上，通过关注外泌体PD-L1包装的机制，动作和对治疗性抗体。特别是，该提案将检验肿瘤细胞可以选择性的总体假设包装PD-L1进入外泌体，以与不同的方式抑制T细胞启动的T细胞启动 PD-L1和PD-1的细胞细胞相互作用通常在肿瘤床中可见。该假设以广泛的形式前提使用体外和体内模型的初步数据表明，包装在包装中的PD-L1的相对分数外泌体与保留在细胞之间的外泌体在细胞系之间有所不同，外泌体PD-L1的抑制可能会导致长期全身性抗肿瘤免疫组织化学，外泌体PD-L1对抗PD-L1抗体具有抗性。测试总体假设提出了以下目的：1）发现选择性的基础机制 PD-L1将PD-L1包装到外泌体中，2）评估外osomemal PD-L1对系统性影响的机械基础免疫，3）剖析外泌体PD-L1如何与其靶细胞相互作用并调节其靶细胞。在AIM 1中，结构/功能并提出了蛋白质组学方法来识别PD-L1包装的调节剂中的外泌体。此外，将使用这些因素的表达与对治疗的抵抗力之间的关联。主要患者样品。在AIM 2中，基于小鼠的免疫方法和患者样本将用于确定在免疫轴外泌体PD-L1功能中的位置。然后将使用发现的见解来发展一种新型的热方法来增强抗肿瘤免疫反应。在AIM 3中，显微镜和功能研究体外模型的研究以及与患者样本的关联研究将用于确定如何外泌体PD-L1与其靶细胞相互作用，可能解释其对抗体的抗性。该提议是非常重要的是，预计将提供可用于识别和治疗大量患者对当前免疫疗法的抗性。虽然该提议着重于子集在特别强调前列腺癌的癌症模型中，发现的范例将是在大多数肿瘤类型中相关。