期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：18
页码：5679-5684
DOI：10.1073/pnas.1418962112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceA recombinant soluble version of the transmembrane death ligand Apo2L/TRAIL has shown compelling preclinical results as a potential cancer therapeutic, but studies in cancer patients have demonstrated little efficacy. Supported membrane display of Apo2L/TRAIL, to mimic the endogenous ligand more faithfully, markedly augments receptor clustering and apoptosis stimulation in cancer cells. Covalent attachment of Apo2L/TRAIL to the surface of liposomes offers a therapeutically tractable approach to membrane display that substantially increases tumor exposure, caspase activation, and antitumor potency. These findings open new avenues for clinical investigation of Apo2L/TRAIL as a cancer therapeutic and may apply to other members of the TNF superfamily, such as FasL and CD70, which are expressed on immune-cell surfaces and are important candidates for cancer immunotherapy. TNF superfamily death ligands are expressed on the surface of immune cells and can trigger apoptosis in susceptible cancer cells by engaging cognate death receptors. A recombinant soluble protein comprising the ectodomain of Apo2 ligand/TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) has shown remarkable preclinical anticancer activity but lacked broad efficacy in patients, possibly owing to insufficient exposure or potency. We observed that antibody cross-linking substantially enhanced cytotoxicity of soluble Apo2L/TRAIL against diverse cancer cell lines. Presentation of the ligand on glass-supported lipid bilayers enhanced its ability to drive receptor microclustering and apoptotic signaling. Furthermore, covalent surface attachment of Apo2L/TRAIL onto liposomes--synthetic lipid-bilayer nanospheres--similarly augmented activity. In vivo, liposome-displayed Apo2L/TRAIL achieved markedly better exposure and antitumor activity. Thus, covalent synthetic-membrane attachment of a cell-surface ligand enhances efficacy, increasing therapeutic potential. These findings have translational implications for liposomal approaches as well as for Apo2L/TRAIL and other clinically relevant TNF ligands.
关键词：cell death ; membrane display ; caspase ; apoptosis ; death receptor
