斯坦福大学医学院Irving L. Weissman团队取得一项新进展。他们的研究发现通过巨噬细胞Siglec-10的CD24信号是肿瘤免疫治疗的靶点。这一研究成果发表在2019年8月15日出版的国际学术期刊《自然》上。

研究人员发现CD24是卵巢癌和乳腺癌中的主要先天免疫检查点，并且是癌症免疫疗法的潜力靶标。研究人员通过与抑制性受体唾液酸结合的Ig样凝集素10（Siglec-10）的相互作用证明肿瘤表达的CD24在促进免疫逃避中的作用，其由肿瘤相关巨噬细胞表达。研究人员发现许多肿瘤高表达CD24，而肿瘤相关巨噬细胞表达高水平的Siglec-10。CD24或Siglec-10基因敲除，以及使用单克隆抗体阻断CD24-Siglec-10相互作用，能够强有力地增强测试过的所有表达CD24人类肿瘤的吞噬作用。CD24的基因敲除和治疗性阻断导致体内巨噬细胞依赖性的肿瘤生长减少以及存活时间增加。这些数据揭示了CD24在几种癌症中是高度表达的抗吞噬信号，并证明了癌症免疫疗法中CD24阻断的治疗潜力。

据悉，卵巢癌和三阴性乳腺癌是影响女性的最致命疾病之一，很少有靶向治疗并存在高转移率。癌细胞能够通过称为“别吃我”信号（包括CD471，程序性细胞死亡配体1（PD-L1）和MHC I复合物的β-2微球蛋白亚基（B2M））的抗吞噬表面蛋白的高表达来逃避巨噬细胞的清除。拮抗“别吃我”信号与其巨噬细胞表达受体相互作用的单克隆抗体已在几种癌症中展现出治疗潜力。然而，对这些药物反应幅度和持久性的差异性表明存在额外的、未知“别吃我”的信号。

附：英文原文

Title: CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy

Author: 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

Issue&Volume: Volume 572 Issue 7769

Abstract: 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 dont eat me signalsincluding CD471, programmed cell death ligand 1 (PD-L1)2 and the beta-2 microglobulin subunit of the major histocompatibility class I complex (B2M)3. Monoclonal antibodies that antagonize the interaction of dont eat me signals with their macrophage-expressed receptors have demonstrated therapeutic potential in several cancers4,5. However, variability in the magnitude and durability of the response to these agents has suggested the presence of additional, as yet unknown dont 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 CD24Siglec-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

Source:https://www.nature.com/articles/s41586-019-1456-0