PAG is a novel target in immunotherapy

PAG是免疫治疗的新靶点

基本信息

批准号：
10265559
负责人：
Adam Mor
金额：
$ 55.87万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-17 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10265559
关键词：
Adaptor Signaling Protein Address Affect Antibodies Biochemical Biological Assay Biology Blocking Antibodies Cell physiology Cells Clinical Clinical Trials Colon Carcinoma Cytoplasmic Tail Data Fluorescence Microscopy Genetic Glycosphingolipids Goals Human Imaging Techniques Immune Immune Targeting Immune checkpoint inhibitor Immune response Immune signaling Immune system Immunization Immunotherapy In Vitro Integral Membrane Protein Intervention Knockout Mice Label Ligand Binding Lipid Bilayers Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of testis Malignant neoplasm of urinary bladder Mediating Membrane Microscopy Modeling Molecular Mutagenesis Pathway interactions Patients Peptides Phosphoproteins Phosphorylation Phosphorylation Site Phosphotransferases Proteins Protocols documentation Published Comment Resolution Resources Role Signal Transduction T-Cell Antigen Receptor Specificity T-Cell Receptor T-Lymphocyte Testing Therapeutic Transgenic Mice Translating Tyrosine anti-PD-1 anti-tumor immune response base cancer cell cancer immunotherapy checkpoint therapy clinical application cytotoxicity experience experimental study immune checkpoint immune checkpoint blockade immunological synapse in vivo innovation malignant breast neoplasm new therapeutic target novel novel therapeutics phosphoproteomics prevent programmed cell death protein 1 receptor recruit response therapeutic candidate tumor tumor growth

项目摘要

PROJECT ABSTRACT Immune checkpoint therapies block inhibitory receptors on T cells to augment anti-tumor immune responses. The Programmed cell Death-1 (PD-1) pathway is a critical inhibitory checkpoint for T cells, and antibodies blocking PD-1 promote immune-mediated identification and clearance of malignant cells. Cancer immunotherapies, including anti-PD-1 antibodies, represent a powerful therapeutic paradigm because they are applicable to a wide variety of tumors and can produce durable clinical responses. Unfortunately, only a fraction of patients demonstrates clinical benefit from current agents. As such, there is an urgent need to develop therapeutics that more effectively target PD-1 signaling as well as other checkpoint inhibitors. We have employed phosphoproteomic protocol to identify proteins that regulate downstream signaling of PD-1. With this approach, we identified the protein PAG as an effector of PD-1 immune checkpoint signaling. We have discovered that PAG is required for PD-1 signaling and inhibition of T cell function and our preliminary genetic and biochemical studies confirm PAG as a target for reversing T cell inhibition. The immediate goal of this proposal is to validate PAG as checkpoint inhibitor candidate. Our long-term goal is to translate our findings and to generate novel immunotherapies for patients with malignancies. We will accomplish these goals with the following aims: Aim 1. Define the mechanism by which PD-1 induces PAG phosphorylation to promote immune checkpoint activation. Using high resolution microscopy, we will determine how PD-1 and PAG cluster at the immunological synapse. Using mutagenesis, we will define the requirement for specific tyrosine within the cytoplasmic region of PAG for PD-1 function and immune synapse clustering. Aim 2. To assess PAG-mediated immune inhibitory potential, in vivo. We will assess tumor growth in syngeneic models using PAG knockout mice. Aim 3. To develop anti-PAG functional antibodies. We will develop strategies to target PAG in vivo. Together, these studies will uncover the mechanism by which PAG mediates inhibitory signals in T cells and its value as a novel target for immune checkpoint blockade.

项目摘要免疫检查点疗法阻止T细胞上的抑制性受体增强抗肿瘤免疫反应。程序性细胞死亡-1（PD-1）途径是T细胞的关键抑制检查点，抗体和抗体阻塞PD-1促进了免疫介导的鉴定和对恶性细胞的清除。癌症免疫疗法，包括抗PD-1抗体，代表了强大的治疗范例，因为它们是适用于多种肿瘤，可产生持久的临床反应。不幸的是，只有一个患者的一部分证明了当前药物的临床益处。因此，迫切需要开发更有效地靶向PD-1信号传导以及其他检查点抑制剂的治疗剂。我们已经采用磷酸蛋白质组学方案来鉴定调节PD-1下游信号传导的蛋白质。通过这种方法，我们将蛋白质PAG确定为PD-1免疫检查点信号传导的效应子。我们已经发现PD-1信号传导和T细胞功能的抑制需要PAG和我们的初步遗传和生化研究证实PAG是逆转T细胞抑制的靶标。直接目标该建议是验证PAG作为检查点抑制剂候选者。我们的长期目标是翻译我们的发现并为恶性肿瘤患者产生新的免疫疗法。我们将完成这些目标以下目的：目标1。定义PD-1诱导PAG磷酸化的机制促进免疫检查点激活。使用高分辨率显微镜，我们将确定PD-1和免疫突触处的PAG集群。使用诱变，我们将定义特定的要求 PD-1功能和免疫突触聚类的PAG细胞质区域内的酪氨酸。目标2 评估PAG介导的免疫抑制潜力，体内。我们将评估合成模型中的肿瘤生长使用PAG淘汰小鼠。目标3。开发抗PAG功能抗体。我们将制定策略靶PAG在体内。总之，这些研究将发现PAG介导抑制性的机制 T细胞中的信号及其作为免疫检查点阻滞的新目标。