Molecular imaging of PD-L1 expression and dynamics with the adnectin-based PET tracer 18F-BMS-986192Stutvoet, T. S., van der Veen, E. L., Kol, A., Antunes, I. F., de Vries, E. F. J., Hospers, G. A. P., de Vries, E. G. E., de Jong, S. & Lub-de Hooge, M. N., 2020, In : Journal of Nuclear Medicine.
Research output: Contribution to journal › Article › Academic › peer-review
18F-BMS-986192, an adnectin-based human programmed cell death ligand 1 (PD-L1) tracer, was developed to non-invasively determine whole-body PD-L1 expression by positron emission tomography (PET). We evaluated usability of 18F-BMS-986192 PET to detect different PD-L1 expression levels and therapy-induced changes of PD-L1 expression in tumors. Methods: In vitro binding assays with 18F-BMS-986192 were performed in human tumor cell lines with different total cellular and membrane PD-L1 protein expression levels. Subsequently, PET imaging was executed in immunodeficient mice xenografted with these cell lines. Mice were treated with interferon gamma (IFNγ) intraperitoneally for 3 days or with the mitogen-activated protein kinase kinase (MEK1/2) inhibitor selumetinib by oral gavage for 24 hours. Thereafter 18F-BMS-986192 was administered intravenously, followed by a 60-minute dynamic PET scan. Tracer uptake was expressed as percentage injected dose per gram tissue (%ID/g). Tissues were collected to evaluate ex vivo tracer biodistribution and to perform flow cytometric, Western blot, and immunohistochemical tumor analyses. Results:18F-BMS-986192 uptake reflected PD-L1 membrane levels in tumor cell lines, and tumor tracer uptake in mice was associated with PD-L1 expression measured immunohistochemically. In vitro IFNγ treatment increased PD-L1 expression in the tumor cell lines and caused up to 12-fold increase in tracer binding. In vivo, IFNγ did neither affect PD-L1 tumor expression measured immunohistochemically nor 18F-BMS-986192 tumor uptake. In vitro, selumetinib downregulated cellular and membrane levels of PD-L1 of tumor cells by 50% as measured by Western blotting and flow cytometry. In mice, selumetinib lowered cellular, but not membrane PD-L1 levels of tumors and consequently no treatment-induced change in 18F-BMS-986192 tumor uptake was observed. Conclusion:18F-BMS-986192 PET imaging allows detection of membrane-expressed PD-L1, as soon as 60 minutes after tracer injection. The tracer can discriminate a range of tumor cell PD-L1 membrane expression levels.
|Journal||Journal of Nuclear Medicine|
|Publication status||E-pub ahead of print - 2020|