Therapeutic Mechanism of CD47 Blockade in Suppressing Melanoma Metastasis

项目摘要 该项目的总体目标是确定分子调节剂，使免疫抑制特性， 转移性黑素瘤和介导CD47阻断抗体的治疗功能的确定的细胞谱系。 我们的中心假设是转移性黑色素瘤细胞通过过度激活 CD47启动子通过NRF1转录因子。CD47的过表达然后调节肿瘤免疫 在某种程度上，抑制黑色素瘤破坏和抗原呈递的专业微环境， 吞噬细胞，同时刺激髓源性抑制细胞（MDSC）， T细胞反应。当拟议的研究完成后，我们将完成识别和 表征调节CD47依赖性免疫逃逸的有效分子和细胞靶标 通过转移黑色素瘤细胞进行监视。描述这些因素也将有助于临床预测 允许基于患者的免疫细胞库选择患者的价值，从而延长治疗时间。 反应和提高生存率。拟议研究的临床意义也突出了以下事实： 我们将使用免疫人源化PDX模型来描述我们在最常见的环境中的发现， 与患者疾病生理相关。

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.