Matlung Hanke L, Szilagyi Katka, Barclay Neil A, van den Berg Timo K
Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
Immunol Rev. 2017 Mar;276(1):145-164. doi: 10.1111/imr.12527.
Immune checkpoint inhibitors, including those targeting CTLA-4/B7 and the PD-1/PD-L1 inhibitory pathways, are now available for clinical use in cancer patients, with other interesting checkpoint inhibitors being currently in development. Most of these have the purpose to promote adaptive T cell-mediated immunity against cancer. Here, we review another checkpoint acting to potentiate the activity of innate immune cells towards cancer. This innate immune checkpoint is composed of what has become known as the 'don't-eat me' signal CD47, which is a protein broadly expressed on normal cells and often overexpressed on cancer cells, and its counter-receptor, the myeloid inhibitory immunoreceptor SIRPα. Blocking CD47-SIRPα interactions has been shown to promote the destruction of cancer cells by phagocytes, including macrophages and neutrophils. Furthermore, there is growing evidence that targeting of the CD47-SIRPα axis may also promote antigen-presenting cell function and thereby stimulate adaptive T cell-mediated anti-cancer immunity. The development of CD47-SIRPα checkpoint inhibitors and the potential side effects that these may have are discussed. Collectively, this identifies the CD47-SIRPα axis as a promising innate immune checkpoint in cancer, and with data of the first clinical studies with CD47-SIRPα checkpoint inhibitors expected within the coming years, this is an exciting and rapidly developing field.
免疫检查点抑制剂，包括那些靶向CTLA-4/B7和PD-1/PD-L1抑制途径的抑制剂，目前已可用于癌症患者的临床治疗，其他一些有趣的检查点抑制剂也正在研发中。其中大多数旨在促进适应性T细胞介导的抗癌免疫。在此，我们综述另一种检查点，它可增强先天免疫细胞对癌症的活性。这种先天免疫检查点由被称为“别吃我”信号的CD47及其反受体——髓系抑制性免疫受体SIRPα组成。CD47是一种在正常细胞上广泛表达且在癌细胞上常过度表达的蛋白质。阻断CD47-SIRPα相互作用已被证明可促进吞噬细胞（包括巨噬细胞和中性粒细胞）对癌细胞的破坏。此外，越来越多的证据表明，靶向CD47-SIRPα轴还可能促进抗原呈递细胞的功能，从而刺激适应性T细胞介导的抗癌免疫。本文讨论了CD47-SIRPα检查点抑制剂的研发及其可能产生的潜在副作用。总的来说，这表明CD47-SIRPα轴是癌症中一个有前景的先天免疫检查点，随着未来几年CD47-SIRPα检查点抑制剂首次临床研究数据的出现，这将是一个令人兴奋且发展迅速的领域。
