Immunotherapy targeting the CD47-SIRPα axis to promote immune clearance of chronic infection

针对 CD47-SIRPα 轴的免疫疗法促进慢性感染的免疫清除

基本信息

批准号：
9123979
负责人：
Michal Caspi Tal
金额：
$ 5.8万
依托单位：
STANFORD UNIVERSITY
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：
2016-04-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9123979
关键词：
Apoptosis Binding CD47 gene CD8B1 gene Cell physiology Cells Chronic Communicable Diseases HIV HIV Infections Highly Active Antiretroviral Therapy Human ITIM Immune Immune response Immune system Immunotherapy In Vitro Individual Infection Inhibitory Synapse Lead Ligands Mediating Mediator of activation protein Modeling Mus NR0B2 gene Natural Killer Cells PDCD1LG1 gene PTPN11 gene Patients Persons Phagocytes Phagocytosis Proteins Reagent SHPS-1 protein Sampling Signal Pathway Signal Transduction Surface T-Lymphocyte Testing Therapeutic Therapeutic Effect Up-Regulation Viral Virus Diseases abstracting cancer cell exhaust exhaustion functional restoration immune clearance in vivo inhibitor/antagonist killings macrophage mouse model novel novel marker overexpression preclinical efficacy prevent public health relevance receptor research study response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The Weissman lab has discovered that cancer cells evade clearance by the immune system through increased expression of CD47, a surface molecule that binds to the inhibitory receptor called signal-regulatory protein alpha (SIRPα) on phagocytic cells, thereby inhibiting phagocytosis. I have found that persistently infected cells in a variety of infectious diseases also upregulate CD47 expression. Furthermore, I discovered that T cells upregulate SIRPα in response to prolonged activation, and together with collaborators have confirmed this in two distinct chronic viral infections. Most strikingly, T cell that upregulate SIRPα also have high expression levels of programmed cell death 1 (PD-1), a mediator of exhaustion. I hypothesize that the CD47-SIRPα axis is an immunomodulatory axis, whereby overexpression of CD47 in infected cells triggers SIRPα mediated blockade of both innate and adaptive immune clearance. This makes the CD47- SIRPα interaction an important target for novel immunotherapies. To this end we have developed multiple reagents to block this interaction, which we will test in vivo in mouse models of chronic infection as well as with human in vitro and patient ex vivo models. I will expand my exploration of SIRPα as a novel marker of T cell exhaustion to determine whether SIRPα is upregulated on exhausted human T cells from HIV infected individuals. I will also investigate the function of SIRPα on T cells. Concurrently w will test whether therapeutic blockade of SIRPα signaling, either alone or in combination with additional inhibitors of T cell exhaustion, can restore functionality of exhausted T cells or lead o clearance of the persistent infection. If successful the proposed experiments will demonstrate the preclinical efficacy of CD47 blockade in infectious diseases, identify a novel marker of T cell exhaustion, and specifically test if targeting the CD47- SIRPα axis can restore functionality to exhausted T cells.

描述（由申请人提供）：Weissman 实验室发现癌细胞通过增加 CD47 的表达来逃避免疫系统的清除，CD47 是一种表面分子，与吞噬细胞上称为信号调节蛋白 α (SIRPα) 的抑制性受体结合，从而我发现持续感染的细胞会抑制吞噬作用。此外，我发现 T 细胞响应长时间激活而上调 SIRPα，并且与合作者一起在两种不同的慢性病毒感染中证实了这一点，最引人注目的是，上调 SIRPα 的 T 细胞也具有高水平。程序性细胞死亡 1 (PD-1) 的表达水平，这是一种耗竭介质，我发现 CD47-SIRPα 轴是免疫调节轴，因此感染细胞中 CD47 过度表达。触发 SIRPα 介导的先天性和适应性免疫清除的阻断，这使得 CD47-SIRPα 相互作用成为新型免疫疗法的重要靶标。为此，我们开发了多种试剂来阻断这种相互作用，我们将在慢性小鼠模型中进行体内测试。我将扩大对 SIRPα 作为 T 细胞耗竭的新标志物的探索，以确定 SIRPα 在 HIV 感染的耗竭的人类 T 细胞上是否上调。我还将测试 SIRPα 对 T 细胞的功能，同时测试 SIRPα 信号传导的治疗性阻断（单独或与 T 细胞耗竭的其他抑制剂联合使用）是否可以恢复耗竭的 T 细胞的功能或导致清除。如果成功，拟议的实验将证明 CD47 阻断在传染病中的临床前功效，并鉴定 T 细胞的新标志物。耗竭，并专门测试靶向 CD47-SIRPα 轴是否可以恢复耗竭 T 细胞的功能。