Cancer Research UK Institute for Cancer Studies, School of Cancer Sciences, University of Birmingham, UK.
Mol Cancer. 2010 Mar 8;9:52. doi: 10.1186/1476-4598-9-52.
CD40 and its ligand (CD40L) play a critical role in co-ordinating immune responses. CD40 is also expressed in lymphoid malignancies and a number of carcinomas. In carcinoma cells the physiological outcome of CD40 ligation depends on the level of receptor engagement with low levels promoting cell survival and high levels inducing cell death. The most profound induction of cell death in carcinoma cells is induced by membrane-bound rather than recombinant soluble CD40L, but like other TNF family ligands, it is cleaved from the membrane by matrix metalloproteinases.
We have generated a replication-deficient adenovirus expressing a mutant CD40L that is resistant to metalloproteinase cleavage such that ligand expression is retained at the cell membrane. Here we show that the mutated, cleavage-resistant form of CD40L is a more potent inducer of apoptosis than wild-type ligand in CD40-positive carcinoma cell lines. Since transgene expression via replication-deficient adenovirus vectors in vivo is low, we have also engineered a conditionally replicating E1A-CR2 deleted adenovirus to express mutant CD40L, resulting in significant amplification of ligand expression and consequent enhancement of its therapeutic effect.
Combined with numerous studies demonstrating its immunotherapeutic potential, these data provide a strong rationale for the exploitation of the CD40-CD40L pathway for the treatment of solid tumours.
CD40 和其配体（CD40L）在协调免疫反应中起着关键作用。CD40 也在淋巴恶性肿瘤和一些癌中表达。在癌细胞中，CD40 配体的生理作用取决于受体的结合水平，低水平促进细胞存活，高水平诱导细胞死亡。在癌细胞中，最显著的细胞死亡诱导是由膜结合而不是重组可溶性 CD40L 引起的，但与其他 TNF 家族配体一样，它通过基质金属蛋白酶从膜上切割下来。
我们生成了一种表达突变型 CD40L 的复制缺陷型腺病毒，该突变型 CD40L 对金属蛋白酶的切割具有抗性，从而使配体表达保留在细胞膜上。在这里，我们表明突变型、不易被切割的 CD40L 比野生型配体在 CD40 阳性癌系中更能诱导细胞凋亡。由于体内复制缺陷型腺病毒载体的转基因表达水平较低，我们还设计了一种条件复制 E1A-CR2 缺失的腺病毒来表达突变型 CD40L，导致配体表达的显著扩增，从而增强其治疗效果。
结合许多研究证明其免疫治疗潜力，这些数据为利用 CD40-CD40L 途径治疗实体瘤提供了强有力的理由。
