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卵巢癌和三阴性乳腺癌是影响女性的致命疾病，靶向疗法极少、转移风险较高。癌细胞能够过度表达被称为“不要吃我”信号的抗吞噬细胞表面蛋白，包括整合素相关蛋白（CD47）、细胞程序性死亡蛋白配体1（PD-L1）、主要组织相容性I类复合物β2微球蛋白亚单位（B2M），从而逃避巨噬细胞的清除作用。抑制“不要吃我”信号与巨噬细胞受体相互作用的单克隆抗体已经对若干癌症表现出治疗潜力。不过，这些药物疗效大小和持久时间的不同，表明还存在其他未知的“不要吃我”信号。 2019年7月31日，全球自然科学三大旗舰期刊之一、英国《自然》正刊在线发表美国斯坦福大学的研究报告表明，热稳定抗原（CD24）可以作为卵巢癌和乳腺癌的主要先天固有免疫检查点，并且有望成为癌症免疫疗法的新靶点。 该研究证实，肿瘤表达的CD24，通过与肿瘤相关巨噬细胞表达的抑制性受体唾液酸结合免疫球蛋白样凝集素10（SIGLEC-10）发生相互作用，从而促进免疫逃逸。随后该研究发现，CD24高表达于卵巢癌、三阴性乳腺癌、激素受体双阳性乳腺癌等许多肿瘤，而SIGLEC-10高表达于肿瘤相关巨噬细胞。通过基因方法清除CD24或SIGLEC-10，或者利用单克隆抗体阻断CD24与SIGLEC-10的相互作用，可以强有力地增强所有CD24阳性人类肿瘤的巨噬细胞吞噬作用，引起体内肿瘤生长减少和生存时间增加。 因此，该研究结果表明，对于卵巢癌、三阴性乳腺癌、激素受体双阳性乳腺癌等癌症，CD24作为高表达的抗吞噬信号，有望成为癌症免疫疗法的新靶点。 Nature. 2019 Jul 31. [Epub ahead of print] CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy. Amira A. Barkal, Rachel E. Brewer, Maxim Markovic, Mark Kowarsky, Sammy A. Barkal, Balyn W. Zaro, Venkatesh Krishnan, Jason Hatakeyama, Oliver Dorigo, Layla J. Barkal, Irving L. Weissman. Stanford University School of Medicine, Stanford, CA, USA; Stanford University, Stanford, CA, USA. Ovarian cancer and triple-negative breast cancer are among the most lethal diseases affecting women, with few targeted therapies and high rates of metastasis. Cancer cells are capable of evading clearance by macrophages through the overexpression of anti-phagocytic surface proteins called 'don't eat me' signals—including CD47, programmed cell death ligand 1 (PD-L1) and the beta-2 microglobulin subunit of the major histocompatibility class I complex (B2M). Monoclonal antibodies that antagonize the interaction of 'don't eat me' signals with their macrophage-expressed receptors have demonstrated therapeutic potential in several cancers. However, variability in the magnitude and durability of the response to these agents has suggested the presence of additional, as yet unknown 'don't eat me' signals. Here we show that CD24 can be the dominant innate immune checkpoint in ovarian cancer and breast cancer, and is a promising target for cancer immunotherapy. We demonstrate a role for tumour-expressed CD24 in promoting immune evasion through its interaction with the inhibitory receptor sialic-acid-binding Ig-like lectin 10 (Siglec-10), which is expressed by tumour-associated macrophages. We find that many tumours overexpress CD24 and that tumour-associated macrophages express high levels of Siglec-10. Genetic ablation of either CD24 or Siglec-10, as well as blockade of the CD24-Siglec-10 interaction using monoclonal antibodies, robustly augment the phagocytosis of all CD24-expressing human tumours that we tested. Genetic ablation and therapeutic blockade of CD24 resulted in a macrophage-dependent reduction of tumour growth in vivo and an increase in survival time. These data reveal CD24 as a highly expressed, anti-phagocytic signal in several cancers and demonstrate the therapeutic potential for CD24 blockade in cancer immunotherapy. DOI: 10.1038/s41586-019-1456-0
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