Therapeutic Mechanism of CD47 Blockade in Suppressing Melanoma Metastasis

项目总结 这个项目的总体目标是确定使免疫抑制特性能够发挥作用的分子调节剂。 转移性黑色素瘤和确定细胞谱系，介导CD47阻断抗体的治疗功能。 我们的中心假设是转移性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的过表达进而调节肿瘤免疫 以一种抑制黑色素瘤破坏和专业人员提呈抗原的方式的微环境 吞噬细胞，同时刺激髓系来源的抑制细胞(MDSCs) T细胞反应。当建议的研究研究完成后，我们将完成识别和 调控CD47依赖的免疫逃逸的有效分子和细胞靶点的特征 通过转移的黑色素瘤细胞进行监测。描绘这些因素也将有助于临床预测 允许根据患者的免疫细胞谱系进行选择以延长治愈时间的价值 反应和提高存活率。这一事实也突显了拟议研究的临床意义 我们将使用免疫人源化的PDX模型来描述我们的发现 在生理上与病人的疾病相关。

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.