Therapeutic Mechanism of CD47 Blockade in Suppressing Melanoma Metastasis

CD47阻断抑制黑色素瘤转移的治疗机制

基本信息

批准号：
10613354
负责人：
ALEXANDER D BOIKO
金额：
$ 37.44万
依托单位：
CEDARS-SINAI MEDICAL CENTER
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：
2020-04-20 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10613354
关键词：
Affect Anti-CD47 Antigen Presentation Area Attention Automobile Driving Binding Biochemical Biological Biological Assay Biological Products Biological Response Modifiers Blocking Antibodies CD47 gene CD47-SIRPα CRISPR/Cas technology Cell Differentiation process Cell Lineage Cell surface Cells ChIP-seq Chemosensitization Cytotoxic T-Lymphocytes DNA Data Detection Disease Frequencies Goals Growth Homeostasis Human Immune Immune Evasion Immunologic Surveillance Immunotherapeutic agent Infiltration Macrophage Activation Mediating Melanoma Cell Metastatic Melanoma Modeling Molecular Molecular Target Myelogenous Myeloid Cells Myeloid-derived suppressor cells Neoplasm Metastasis Organism PTPNS1 gene Pathogenesis Patient Selection Patients Phagocytes Physiological Predictive Value Production Property Publications Reactive Oxygen Species Recurrent disease Regimen Regulation Resistance development Role Signal Transduction Surface Antigens T cell response T-Cell Proliferation T-Lymphocyte Therapeutic Time Tissues Transgenes Up-Regulation adaptive immune response anti-cancer cell type cellular targeting clinical predictors clinically relevant clinically significant design effector T cell in vivo innate immune checkpoint melanocyte melanoma negative affect neoplastic cell nuclear respiratory factor overexpression patient derived xenograft model programmed cell death protein 1 promoter receptor research study response therapeutically effective transcription factor treatment response tumor tumor growth tumor microenvironment tumor-immune system interactions virtual

项目摘要

PROJECT SUMMARY The overall goal of this project is to identify molecular regulators enabling immune suppressive properties of metastatic melanoma and define cell lineages that mediate therapeutic function of CD47 blocking antibodies. Our central hypothesis is that metastasizing melanoma cells avoid immune recognition by hyperactivating CD47 promoter through NRF1 transcription factor. Overexpression of CD47 then modulates tumor immune microenvironment in a way that inhibits melanoma destruction and antigen presentation by professional phagocytes while at the same time stimulating myeloid derived suppressive cells (MDSCs) that negatively affect T-Cell responses. When the proposed research studies are completed we will accomplish identification and characterization of potent molecular and cellular targets that regulate CD47 dependent escape of immune surveillance by metastasizing melanoma cells. Delineating these factors will also serve a clinically predictive value to allow patient selection based on their immune cell repertoire resulting in the prolonged curative responses and increased survival. Clinical significance of the proposed studies is also highlighted by the fact that we will be using immune- humanized PDX models to characterize our findings in the setting most physiologically relevant to the patient disease.

项目概要该项目的总体目标是确定能够实现免疫抑制特性的分子调节剂转移性黑色素瘤并定义介导 CD47 阻断抗体治疗功能的细胞谱系。我们的中心假设是，转移的黑色素瘤细胞通过过度激活来避免免疫识别 CD47 启动子通过 NRF1 转录因子。 CD47 的过度表达随后调节肿瘤免疫专业人士以抑制黑色素瘤破坏和抗原呈递的方式调节微环境吞噬细胞，同时刺激骨髓源性抑制细胞 (MDSC)，从而产生负面影响 T 细胞反应。当拟议的研究完成后，我们将完成识别和调节 CD47 依赖性免疫逃逸的有效分子和细胞靶标的表征通过转移黑色素瘤细胞进行监测。描述这些因素也将有助于临床预测允许根据患者的免疫细胞库进行选择，从而延长疗效反应并提高生存率。以下事实也凸显了拟议研究的临床意义我们将使用免疫人源化 PDX 模型来描述我们在最常见环境中的发现与患者疾病有生理相关性。