Novel mechanisms regulating PD-1 signaling and function

调节 PD-1 信号传导和功能的新机制

基本信息

批准号：
10522391
负责人：
Adam Mor
金额：
$ 44.22万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-20 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10522391
关键词：
Address Adverse event Antibodies Arthritis Biochemical Biology Blocking Antibodies Cell physiology Cells Clinical Clinical Trials Complex Cytoplasmic Tail Data Enzymes Event Failure Future Genetic Goals Grant Human Immune Immune response Immune system Immunotherapy In Vitro Inflammatory Inflammatory Response Intervention Knockout Mice Ligand Binding MAP Kinase Gene MAP3K7 gene Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of pancreas Mass Spectrum Analysis Mediating Methods Modeling Molecular Mus PTPN11 gene Pathway interactions Patients Pharmacology Phenotype Phosphorylation Phosphotransferases Population Prognosis Protein Binding Domain Proteins Public Health Publications Publishing Renal carcinoma Resistance Role Sequence Analysis Signal Pathway Signal Transduction Structure T-Cell Proliferation T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Toxic effect Work anti-PD-1 anti-tumor immune response base cancer cell cancer immunotherapy checkpoint therapy cytokine design experience experimental study imaging approach immune checkpoint blockade immune-related adverse events in silico in vivo innovation kinase inhibitor neoplastic cell new technology novel novel therapeutics phosphoproteomics preclinical development predicting response prediction algorithm programmed cell death protein 1 receptor response success targeted treatment tumor tumor growth tumor progression

项目摘要

ABSTRACT Cancer immunotherapies represent a powerful and newly emergent therapeutic paradigm, both because of their durable clinical responses and applicability to a wide variety of tumors. Immune checkpoint therapies block inhibitory receptors on T cells in order to augment anti-tumor immune responses. Programmed cell death protein 1 (PD-1) is a critical inhibitory checkpoint for T cells. The identification and clearance of malignant cells can be brought about by antibodies which block PD-1. Despite the success of these antibodies, most patients do not respond to PD-1 blockade, and many experience immune-related adverse events. New studies indicate that some 5-10% of patients demonstrate accelerated cancer progression after anti-PD-1 treatment, in contrast to predicted responses based on current mechanistic models. With both the potential successes and failures of PD-1 being so significant, the need to understand PD-1 signaling is evidently very urgent, both for explaining the mechanism of clinical responses and for developing therapeutics that go beyond simply interfering with ligand binding. We have developed a new method to analyze mass spectrometry data and discovered novel effectors of PD-1 signaling. Most excitingly, we have identified multiple candidates, including the kinase VRK2 which we intend to investigate further. The overarching goal of this proposal is to study PD-1-associated kinases in order to better define novel signaling pathways and to uncover T cell-intrinsic mechanisms which contribute to resistance to PD-1 blockade. In the first aim, we will discover the molecular mechanism by which VRK2 controls PD-1 signaling in T cells. We will perform structure-function analyses to test the hypothesis that VRK2’s enzymatic domain is required for mediating specific PD-1 functions and utilize biochemical and imaging approaches to uncover the contribution made by VRK2 interactions with MAPK8IP1 and MAP3K7 towards PD-1 signaling. In the second aim we will test the hypothesis that VRK2 is required for PD-1 inhibition of cellular functions in vivo. We will utilize VRK2 KO mice to uncover the mechanism by which VRK2 supports tumor growth in vivo in the context of PD-1 blockade and resistance. Given the large impact of PD- 1 on public health, the proposed work is incredibly significant.

抽象的癌症免疫疗法代表了一种强大而新兴的治疗范式，既有其耐用性对各种肿瘤的临床反应和适用性。免疫检查点疗法阻断抑制受体在T细胞上以增加抗肿瘤免疫复杂。程序性细胞死亡蛋白1（PD-1）是一种关键的抑制 T细胞的检查点。恶性细胞的识别和清除率可以通过阻塞的抗体引起 PD-1。尽管这些抗体取得了成功，但大多数患者对PD-1封锁没有反应，并且许多经验与免疫相关的广告活动。新研究表明，约有5-10％的患者表现出加速癌症。抗PD-1处理后的进展与基于当前机械模型的预测反应相反。两者 PD-1的潜在成功和失败是如此重要，了解PD-1信号的需求显然非常非常紧急的是解释临床反应的机制，又用于开发不仅仅是简单的疗法干扰配体结合。我们开发了一种新方法来分析质谱数据并发现 PD-1信号传导的新作用。最令人兴奋的是，我们已经确定了多个候选人，包括激酶VRK2 我们打算进一步研究。该提案的总体目标是研究与PD-1相关激酶，以便为了更好地定义新的信号通路和发现T细胞内部机制，这有助于对PD-1的抗性 glocade。在第一个目标中，我们将发现VRK2控制T细胞中PD-1信号传导的分子机制。我们将进行结构功能分析，以测试介导所必需的VRK2酶结构域的假设特定的PD-1功能并利用生化和成像方法来发现VRK2所做的贡献与MAPK8IP1和MAP3K7相互作用，朝PD-1信号传导。在第二个目标中，我们将检验以下假设：VRK2 PD-1在体内抑制细胞功能所必需的。我们将利用VRK2 KO小鼠来揭示该机制在PD-1阻滞和抗性的背景下，VRK2支持体内肿瘤的生长。鉴于PD的影响很大 1关于公共卫生，拟议的工作非常重要。