Agonist Anti-CD137 mAb Act on Tumor Endothelial Cells to Enhance Recruitment of Activated T Lymphocytes
Agonist Anti-CD137 mAb Act on Tumor Endothelial Cells to Enhance Recruitment of Activated T Lymphocytes
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DOI：
10.1158/0008-5472.can-10-1733
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发表时间：
2011-02-01
期刊：
影响因子：
11.2
通讯作者：
Melero, Ignacio
中科院分区：
文献类型：
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作者：
Palazon, Asis;Teijeira, Alvaro;Melero, Ignacio
免疫共刺激分子CD 137（也称为4-1BB）的激动剂单克隆抗体（mAb）目前正处于癌症治疗的临床试验中，其基于其对引发的T细胞和可能的免疫系统的其他细胞的共刺激作用。在这里，我们提供的证据表明，CD 137选择性地表达在肿瘤内皮细胞的表面。缺氧上调小鼠内皮细胞上的CD 137。用激动剂CD 137 mAb治疗荷瘤免疫功能低下的Rag（-/-）小鼠未引起任何可测量的抗血管生成作用。相反，激动剂mAb刺激肿瘤内皮细胞，增加细胞表面粘附分子细胞间粘附分子（ICAM）-1，血管细胞粘附分子（VCAM）-1，E-选择素的表达。当过继转移到小鼠体内时，来自CD 137缺陷动物的活化T淋巴细胞在用激动剂mAb治疗后更积极地进入肿瘤组织。这种作用可被抗ICAM-1和抗VCAM-1阻断抗体中和。因此，CD 137的刺激不仅增强了T细胞活化，而且通过直接作用于冲洗肿瘤的血管，增加了它们向恶性组织的运输。我们的研究结果确定了一个额外的作用机制，可以解释激动剂CD 137抗体的免疫抑制作用。Cancer Res; 71（3）; 801-11. (C)2011年AACR。
Agonist monoclonal antibodies (mAb) to the immune costimulatory molecule CD137, also known as 4-1BB, are presently in clinical trials for cancer treatment on the basis of their costimulatory effects on primed T cells and perhaps other cells of the immune system. Here we provide evidence that CD137 is selectively expressed on the surface of tumor endothelial cells. Hypoxia upregulated CD137 on murine endothelial cells. Treatment of tumor-bearing immunocompromised Rag(-/-) mice with agonist CD137 mAb did not elicit any measurable antiangiogenic effects. In contrast, agonist mAb stimulated tumor endothelial cells, increasing cell surface expression of the adhesion molecules intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin. When adoptively transferred into mice, activated T lymphocytes derived from CD137-deficient animals entered more avidly into tumor tissue after treatment with agonist mAb. This effect could be neutralized with anti-ICAM-1 and anti-VCAM-1 blocking antibodies. Thus, stimulation of CD137 not only enhanced T-cell activation but also augmented their trafficking into malignant tissue, through direct actions on the blood vessels that irrigate the tumor. Our findings identify an additional mechanism of action that can explain the immunotherapeutic effects of agonist CD137 antibodies. Cancer Res; 71(3); 801-11. (C) 2011 AACR.