Department of Pathology, Stanford University Medical Center, Stanford, CA 94305, USA.
Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6656-61. doi: 10.1073/pnas.1121629109. Epub 2012 Mar 26.
Antibodies against CD47, which block tumor cell CD47 interactions with macrophage signal regulatory protein-α, have been shown to decrease tumor size in hematological and epithelial tumor models by interfering with the protection from phagocytosis by macrophages that intact CD47 bestows upon tumor cells. Leiomyosarcoma (LMS) is a tumor of smooth muscle that can express varying levels of colony-stimulating factor-1 (CSF1), the expression of which correlates with the numbers of tumor-associated macrophages (TAMs) that are found in these tumors. We have previously shown that the presence of TAMs in LMS is associated with poor clinical outcome and the overall effect of TAMs in LMS therefore appears to be protumorigenic. However, the use of inhibitory antibodies against CD47 offers an opportunity to turn TAMs against LMS cells by allowing the phagocytic behavior of resident macrophages to predominate. Here we show that interference with CD47 increases phagocytosis of two human LMS cell lines, LMS04 and LMS05, in vitro. In addition, treatment of mice bearing subcutaneous LMS04 and LMS05 tumors with a novel, humanized anti-CD47 antibody resulted in significant reductions in tumor size. Mice bearing LMS04 tumors develop large numbers of lymph node and lung metastases. In a unique model for neoadjuvant treatment, mice were treated with anti-CD47 antibody starting 1 wk before resection of established primary tumors and subsequently showed a striking decrease in the size and number of metastases. These data suggest that treatment with anti-CD47 antibodies not only reduces primary tumor size but can also be used to inhibit the development of, or to eliminate, metastatic disease.
针对 CD47 的抗体可阻断肿瘤细胞 CD47 与巨噬细胞信号调节蛋白-α的相互作用，已被证明可通过干扰巨噬细胞吞噬作用来减少血液系统和上皮肿瘤模型中的肿瘤大小，而完整的 CD47 可赋予肿瘤细胞这种吞噬作用的保护。平滑肌肉瘤（LMS）是一种平滑肌肿瘤，可表达不同水平的集落刺激因子-1（CSF1），其表达与这些肿瘤中发现的肿瘤相关巨噬细胞（TAMs）的数量相关。我们之前已经表明，LMS 中 TAMs 的存在与不良临床结局相关，因此 TAMs 在 LMS 中的总体影响似乎是促肿瘤的。然而，使用针对 CD47 的抑制性抗体提供了一个机会，可以通过允许常驻巨噬细胞的吞噬行为占主导地位，将 TAMs 转化为针对 LMS 细胞。在这里，我们表明干扰 CD47 可增加两种人 LMS 细胞系 LMS04 和 LMS05 的体外吞噬作用。此外，用一种新型人源化抗 CD47 抗体治疗皮下携带 LMS04 和 LMS05 肿瘤的小鼠导致肿瘤体积显著减小。携带 LMS04 肿瘤的小鼠会发展出大量的淋巴结和肺转移。在新辅助治疗的独特模型中，从切除已建立的原发性肿瘤前 1 周开始，用抗 CD47 抗体治疗小鼠，随后明显减少了转移瘤的大小和数量。这些数据表明，抗 CD47 抗体的治疗不仅可减少原发性肿瘤的大小，而且还可用于抑制转移性疾病的发展或消除转移性疾病。
