Melo Garcia Luciana, Barabé Frédéric
MD Anderson Cancer Center, Department of Stem Cell Transplantation and Cellular Therapy, University of Texas, Houston, TX 77030, USA.
Centre Hospitalier Universitaire de Québec-Université Laval, Québec, QC G1V 4G2, Canada.
Cancers (Basel). 2021 Dec 13;13(24):6258. doi: 10.3390/cancers13246258.
CD47 is a surface membrane protein expressed by all normal tissues. It is the so-called "don't eat me signal" because it protects the cells against phagocytosis. The CD47 interacts with the signal regulatory protein alpha (SIRPα) on the surface of macrophages, leading to downstream inhibitory signaling that dampens phagocytic capacity. Since macrophages exert immune surveillance against cancers, cancer cells overexpress CD47 to defend themselves against phagocytosis. Acute myeloid leukemia (AML) is a cancer of hematopoietic stem/progenitor cells (HSPC), and similar to other types of cancers, leukemic blasts show enhanced levels of CD47. In patients with AML, CD47 has been associated with a higher disease burden and poor overall survival. Blockage of CD47-SIRPα signaling leads to improved phagocytosis of AML cells and better overall survival in xenograft models. However, the introduction of a pro-phagocytic signal is needed to induce greater phagocytic capacity. These pro-phagocytic signals can be either Fc receptor stimulants (such as monoclonal antibodies) or natural pro-phagocytic molecules (such as calreticulin). Based on these pre-clinical findings, various clinical trials investigating the blockade of CD47-SIRPα interaction have been designed as monotherapy and in combination with other anti-leukemic agents. In this review, we will discuss CD47 biology, highlight its implications for AML pathophysiology, and explore the potential clinical translation of disrupting CD47-SIRPα to treat patients with AML.
CD47是一种由所有正常组织表达的表面膜蛋白。它就是所谓的“别吃我信号”，因为它能保护细胞免受吞噬作用。CD47与巨噬细胞表面的信号调节蛋白α（SIRPα）相互作用，导致下游抑制性信号传导，从而抑制吞噬能力。由于巨噬细胞对癌症发挥免疫监视作用，癌细胞会过度表达CD47以抵御吞噬作用。急性髓系白血病（AML）是造血干/祖细胞（HSPC）的癌症，与其他类型的癌症类似，白血病原始细胞显示出CD47水平升高。在AML患者中，CD47与更高的疾病负担和较差的总生存率相关。阻断CD47-SIRPα信号传导可改善AML细胞的吞噬作用，并在异种移植模型中提高总生存率。然而，需要引入促吞噬信号来诱导更大的吞噬能力。这些促吞噬信号可以是Fc受体刺激剂（如单克隆抗体）或天然促吞噬分子（如钙网蛋白）。基于这些临床前研究结果，已经设计了各种研究阻断CD47-SIRPα相互作用的临床试验，作为单一疗法或与其他抗白血病药物联合使用。在本综述中,我们将讨论CD47的生物学特性,强调其对AML病理生理学的影响,并探讨破坏CD47-SIRPα以治疗AML患者的潜在临床转化应用。
