Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
Department of Molecular Medicine II, Heinrich Heine University Dösseldorf, Dösseldorf, Germany.
Cancer Immunol Res. 2015 Feb;3(2):184-95. doi: 10.1158/2326-6066.CIR-14-0113. Epub 2014 Dec 19.
The B7 family plays a critical role in both positive and negative regulation of immune responses by engaging a variety of receptors on lymphocytes. Importantly, blocking coinhibitory molecules using antibodies specific for CTLA-4 and PD-1 enhances tumor immunity in a subset of patients. Therefore, it is critical to understand the role of different B7 family members since they may be suitable therapeutic targets. B7-H4 is another member that inhibits T-cell function, and it is also upregulated on a variety of tumors and has been proposed to promote tumor growth. Here, we investigate the role of B7-H4 in tumor development and show that B7-H4 expression inhibits tumor growth in two mouse models. Furthermore, we show that B7-H4 expression is required for antitumor immune responses in a mouse model of mammary tumorigenesis. We found that the expression levels of B7-H4 correlate with MHC class I expression in both mouse and human samples. We show that IFNγ upregulates B7-H4 expression on mouse embryo fibroblasts and that the upregulation of B7-H4 on tumors is dependent on T cells. Notably, patients with breast cancer with increased B7-H4 expression show a prolonged time to recurrence. These studies demonstrate a positive role for B7-H4 in promoting antitumor immunity.
B7 家族在通过淋巴细胞上的各种受体参与正调节和负调节免疫应答方面发挥着关键作用。重要的是，使用针对 CTLA-4 和 PD-1 的抗体阻断共抑制分子可增强部分患者的肿瘤免疫力。因此，了解不同 B7 家族成员的作用至关重要，因为它们可能是合适的治疗靶点。B7-H4 是另一种抑制 T 细胞功能的成员，它在多种肿瘤上也上调，并被提议促进肿瘤生长。在这里，我们研究了 B7-H4 在肿瘤发展中的作用，并表明 B7-H4 表达在两种小鼠模型中抑制肿瘤生长。此外，我们表明 B7-H4 表达是在乳腺肿瘤发生的小鼠模型中抗肿瘤免疫反应所必需的。我们发现 B7-H4 的表达水平与 MHC I 类在小鼠和人类样本中的表达相关。我们表明 IFNγ 上调小鼠胚胎成纤维细胞上的 B7-H4 表达，并且肿瘤上的 B7-H4 上调依赖于 T 细胞。值得注意的是，B7-H4 表达增加的乳腺癌患者复发时间延长。这些研究表明 B7-H4 在促进抗肿瘤免疫方面发挥积极作用。
