INSERM UMR 837, 1, rue Polonovski, 59045 Lille, France.
Mol Cancer. 2011 Aug 31;10:105. doi: 10.1186/1476-4598-10-105.
Tumor cells can escape the immune system by overexpressing molecules of the B7 family, e.g. B7-H1 (PD-L1 or CD86), which suppresses the anti-tumor T-cell responses through binding to the PD-1 receptor, and similarly for B7.1 (CD80), through binding to CTLA-4. Moreover, direct interactions between B7-H1 and B7.1 molecules are also likely to participate in the immunoevasion mechanism. In this study, we used a mouse model of tumor dormancy, DA1-3b leukemia cells. We previously showed that a minor population of DA1-3b cells persists in equilibrium with the immune system for long periods of time, and that the levels of surface expression of B7-H1 and B7.1 molecules correlates with the dormancy time. We found that leukemia cells DA1-3b/d365 cells, which derived from long-term dormant tumors and overexpressed B7-H1 and B7.1 molecules, were highly permissive to Ad5FB4, a human adenovirus serotype 5 (Ad5) vector pseudotyped with chimeric human-bovine fibers. Both B7-H1 and B7.1 were required for Ad5FB4-cell binding and entry, since (i) siRNA silencing of one or the other B7 gene transcript resulted in a net decrease in the cell binding and Ad5FB4-mediated transduction of DA1-3b/d365; and (ii) plasmid-directed expression of B7.1 and B7-H1 proteins conferred to Ad5FB4-refractory human cells a full permissiveness to this vector. Binding data and flow cytometry analysis suggested that B7.1 and B7-H1 molecules played different roles in Ad5FB4-mediated transduction of DA1-3b/d365, with B7.1 involved in cell attachment of Ad5FB4, and B7-H1 in Ad5FB4 internalization. BRET analysis showed that B7.1 and B7-H1 formed heterodimeric complexes at the cell surface, and that Ad5FB4 penton, the viral capsomere carrying the fiber projection, could negatively interfere with the formation of B7.1/B7-H1 heterodimers, or modify their conformation. As interactors of B7-H1/B7.1 molecules, Ad5FB4 particles and/or their penton capsomeres represent potential therapeutic agents targeting cancer cells that had developed immunoevasion mechanisms.
肿瘤细胞可以通过过度表达 B7 家族分子来逃避免疫系统，例如 B7-H1（PD-L1 或 CD86），它通过与 PD-1 受体结合抑制抗肿瘤 T 细胞反应，B7.1（CD80）也是如此，通过与 CTLA-4 结合。此外，B7-H1 和 B7.1 分子之间的直接相互作用也可能参与免疫逃逸机制。在这项研究中，我们使用了肿瘤休眠的小鼠模型，即 DA1-3b 白血病细胞。我们之前表明，一小部分 DA1-3b 细胞与免疫系统保持平衡，可以长时间休眠，并且表面表达 B7-H1 和 B7.1 分子的水平与休眠时间相关。我们发现，源自长期休眠肿瘤且过度表达 B7-H1 和 B7.1 分子的白血病细胞 DA1-3b/d365 细胞对 Ad5FB4 高度允许，Ad5FB4 是一种用人腺病毒血清型 5（Ad5）载体假型化的嵌合人牛纤维。B7-H1 和 B7.1 都需要用于 Ad5FB4-细胞结合和进入，因为 (i) 一种或另一种 B7 基因转录本的 siRNA 沉默导致 DA1-3b/d365 的细胞结合和 Ad5FB4 介导的转导净减少；和 (ii) 质粒指导的 B7.1 和 B7-H1 蛋白的表达赋予对 Ad5FB4 有抗性的人细胞对该载体的完全允许性。结合数据和流式细胞术分析表明，B7.1 和 B7-H1 分子在 Ad5FB4 介导的 DA1-3b/d365 转导中发挥不同的作用，B7.1 参与 Ad5FB4 的细胞附着，B7-H1 参与 Ad5FB4 的内化。BRET 分析表明，B7.1 和 B7-H1 在细胞表面形成异二聚体复合物，并且 Ad5FB4 五聚体，携带纤维突起的病毒衣壳，可负干扰 B7.1/B7-H1 异二聚体的形成，或修饰其构象。作为 B7-H1/B7.1 分子的相互作用物，Ad5FB4 颗粒和/或其五聚体衣壳代表针对已发展出免疫逃逸机制的癌细胞的潜在治疗剂。
