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Abstract：
Neuroblastoma is a pediatric cancer with significant clinical heterogeneity. Despite extensive efforts, it is still difficult to cure children with high-risk neuroblastoma. Immunotherapy is a promising approach to treat children with this devastating disease. We have previously reported that macrophages are important effector cells in high-risk neuroblastoma. In this perspective article, we discuss the potential function of the macrophage inhibitory receptor SIRPA in the homeostasis of tumor-associated macrophages in high-risk neuroblastoma. The ligand of SIRPA is CD47, known as a \"don\'t eat me\" signal, which is highly expressed on cancer cells compared to normal cells. CD47 is expressed on both tumor and stroma cells, whereas SIRPA expression is restricted to macrophages in high-risk neuroblastoma tissues. Notably, high SIRPA expression is associated with better disease outcome. According to the current paradigm, the interaction between CD47 on tumor cells and SIRPA on macrophages leads to the inhibition of tumor phagocytosis. However, data from recent clinical trials have called into question the use of anti-CD47 antibodies for the treatment of adult and pediatric cancers. The restricted expression of SIRPA on macrophages in many tissues argues for targeting SIRPA on macrophages rather than CD47 in CD47/SIRPA blockade therapy. Based on the data available to date, we propose that disruption of the CD47-SIRPA interaction by anti-CD47 antibody would shift the macrophage polarization status from M1 to M2, which is inferred from the 1998 study by Timms et al. In contrast, the anti-SIRPA F(ab\')2 lacking Fc binds to SIRPA on the macrophage, mimics the CD47-SIRPA interaction, and thus maintains M1 polarization. Anti-SIRPA F(ab\')2 also prevents the binding of CD47 to SIRPA, thereby blocking the \"don\'t eat me\" signal. The addition of tumor-opsonizing and macrophage-activating antibodies is expected to enhance active tumor phagocytosis.
摘要：
神经母细胞瘤是一种具有显著临床异质性的儿科癌症。尽管付出了广泛的努力，高危神经母细胞瘤患儿仍难以治愈。免疫疗法是治疗患有这种毁灭性疾病的儿童的有希望的方法。我们以前曾报道，巨噬细胞是高危神经母细胞瘤中重要的效应细胞。在这篇透视文章中，我们讨论了巨噬细胞抑制性受体SIRPA在高危神经母细胞瘤肿瘤相关巨噬细胞稳态中的潜在功能.SIRPA的配体是CD47，被称为“不要吃我”信号，与正常细胞相比，在癌细胞上高表达。CD47在肿瘤和基质细胞上表达，而SIRPA的表达仅限于高危神经母细胞瘤组织中的巨噬细胞。值得注意的是,高SIRPA表达与更好的疾病预后相关。根据目前的范式,肿瘤细胞上的CD47与巨噬细胞上的SIRPA之间的相互作用导致肿瘤吞噬作用的抑制。然而,最近的临床试验数据对使用抗CD47抗体治疗成人和儿童癌症提出了质疑.SIRPA在许多组织中的巨噬细胞上的限制性表达表明在CD47/SIRPA阻断疗法中在巨噬细胞上靶向SIRPA而不是CD47。根据迄今为止可用的数据，我们提出,抗CD47抗体破坏CD47-SIRPA相互作用会使巨噬细胞极化状态从M1转变为M2,这是由Timms等人1998年的研究推断的.相比之下,缺乏Fc的抗SIRPAF（ab'）2与巨噬细胞上的SIRPA结合，模拟CD47-SIRPA相互作用，从而保持M1极化。抗SIRPAF(ab')2也阻止CD47与SIRPA的结合，从而阻止了“不要吃我”的信号。肿瘤调理和巨噬细胞激活抗体的添加有望增强活跃的肿瘤吞噬作用。
