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

• 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
• 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

 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CD 47的表达逃避免疫系统的清除，CD 47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，从而抑制吞噬作用。我发现，持续感染的细胞， 多种感染性疾病也上调CD 47表达。此外，我发现T细胞上调SIRPα以响应长期激活，并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细胞也具有高表达水平的程序性细胞死亡1（PD-1），其是耗竭的介导物。我假设CD 47-SIRPα轴是一个免疫调节轴，由此感染细胞中CD 47的过表达触发SIRPα介导的先天性和适应性免疫清除的阻断。这使得CD 47- SIRPα相互作用成为新型免疫疗法的重要靶标。为此，我们已经开发了多种试剂来阻断这种相互作用，我们将在慢性感染的小鼠模型以及人类体外和患者离体模型中进行体内测试。我将扩展我对SIRPα作为T细胞耗竭的新标志物的探索，以确定SIRPα是否在来自HIV感染个体的耗竭的人类T细胞上上调。我们还将研究SIRPα在T细胞上的功能。同时，我们将测试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组合）是否可以恢复耗竭的T细胞的功能或导致持续性感染的清除。如果成功的话，所提出的实验将证明CD 47阻断在感染性疾病中的临床前功效，鉴定T细胞的新标志物， 本发明的目的是检测靶向CD 47- SIRPα轴是否可以恢复耗尽的T细胞的功能。