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：针对免疫检查点蛋白 PD-L1 和 PD-1 的抗体彻底改变了癌症治疗方法导致许多以前被认为无法治愈的患者得到持久缓解。保持耐药性，并且癌症类型的反应率可能有很大差异，因此，迫切需要做到这一点。了解反应的变化以改善癌症护理该提案汇集了一个团队。在基础科学、转化科学和临床科学方面具有互补专业知识的研究人员，他们拥有共同的长期研究成果目标是寻找新的方法来对癌症治疗的最新结果进行分类和个性化。研究人员认为外泌体中免疫检查点蛋白的包装在免疫检查点蛋白的基础上发挥着重要作用患者对免疫检查点抑制剂的反应存在差异，具体来说，PD-L1 的量不同。可以被运输到外泌体，而外泌体又可以在一定距离外发挥作用，抑制抗肿瘤 T 细胞功能，从而使即使在对抗 PD-L1 治疗耐药的模型中，肿瘤进展也是如此。该提案的目的是建立一个模型。通过关注外泌体 PD-L1 包装、作用和耐药性的机制来研究这些发现特别是，该提案将检验肿瘤细胞可以选择性地进行的总体假设。将 PD-L1 包装到外泌体中，以一种不同于外泌体的方式抑制远端 T 细胞的启动 PD-L1 和 PD-1 的细胞间相互作用通常出现在肿瘤床中，该假设的前提是广泛。使用体外和体内模型的初步数据表明，包装中的 PD-L1 的相对分数外泌体与保留在细胞中的情况因细胞系而异，抑制外泌体 PD-L1 可能会导致长期全身抗肿瘤免疫，并且外泌体PD-L1对抗PD-L1抗体具有抵抗力。总体假设，提出以下目标：1）揭示选择性的机制将PD-L1包装到外泌体中，2）评估外泌体PD-L1对全身影响的机制基础免疫，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。目标 1，结构/功能。提出了蛋白质组学方法来识别 PD-L1 包装到外泌体中的调节因子。此外，将使用以下方法评估这些因子的表达与治疗耐药性之间的关联在目标 2 中，将使用基于小鼠的免疫学方法和患者样本。确定外泌体 PD-L1 功能在免疫轴中的哪个位置，然后将用于开发。目标 3：显微镜和功能性增强抗肿瘤免疫反应的新治疗方法。体外模型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了其对抗体的抵抗力。非常重要，因为它有望提供新的基础知识，可用于识别和治疗大部分对当前免疫疗法有抵抗力的患者，而该提案侧重于一小部分患者。特别强调前列腺癌的癌症模型，所发现的范式预计将是与大多数（如果不是所有）肿瘤类型相关。