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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.

项目简介: