18F-FDG PET Visualizes Systemic STING Agonist-Induced Lymphocyte Activation in Preclinical Models
| Autor: | Thuc M. Le, Hailey R. Lee, Evan R. Abt, Khalid Rashid, Amanda L. Creech, Keke Liang, Jing Cui, Arthur Cho, Liu Wei, Amanda Labora, Charlotte Chan, Eric Sanchez, Kriti Kriti, Daniel Karin, Luyi Li, Nanping Wu, Christine Mona, Giuseppe Carlucci, Willy Hugo, Ting-Ting Wu, Timothy R. Donahue, Johannes Czernin, Caius G. Radu |
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| Rok vydání: | 2023 |
| Předmět: |
Male
lymphocytes Inflammatory and immune system immunometabolism Clinical Sciences Inbred C57BL Lymphocyte Activation STING agonists immune activation Basic Science Investigation Vaccine Related Mice Nuclear Medicine & Medical Imaging Fluorodeoxyglucose F18 Positron-Emission Tomography Genetics Animals Biomedical Imaging Radiology Nuclear Medicine and imaging Signal Transduction 18F-FDG PET Cancer |
| Zdroj: | Journal of nuclear medicine : official publication, Society of Nuclear Medicine, vol 64, iss 1 J Nucl Med |
| Popis: | Stimulator of interferon genes (STING) is a mediator of immune recognition of cytosolic DNA, which plays important roles in cancer, cytotoxic therapies, and infections with certain pathogens. Although pharmacologic STING activation stimulates potent antitumor immune responses in animal models, clinically applicable pharmacodynamic biomarkers that inform of the magnitude, duration, and location of immune activation elicited by systemic STING agonists are yet to be described. We investigated whether systemic STING activation induces metabolic alterations in immune cells that can be visualized by PET imaging. Methods: C57BL/6 mice were treated with systemic STING agonists and imaged with (18)F-FDG PET after 24 h. Splenocytes were harvested 6 h after STING agonist administration and analyzed by single-cell RNA sequencing and flow cytometry. (18)F-FDG uptake in total splenocytes and immunomagnetically enriched splenic B and T lymphocytes from STING agonist–treated mice was measured by γ-counting. In mice bearing prostate or pancreas cancer tumors, the effects of STING agonist treatment on (18)F-FDG uptake, T-lymphocyte activation marker levels, and tumor growth were evaluated. Results: Systemic delivery of structurally distinct STING agonists in mice significantly increased (18)F-FDG uptake in the spleen. The average spleen SUV(max) in control mice was 1.90 (range, 1.56–2.34), compared with 4.55 (range, 3.35–6.20) in STING agonist–treated mice (P < 0.0001). Single-cell transcriptional and flow cytometry analyses of immune cells from systemic STING agonist–treated mice revealed enrichment of a glycolytic transcriptional signature in both T and B lymphocytes that correlated with the induction of immune cell activation markers. In tumor-bearing mice, STING agonist administration significantly delayed tumor growth and increased (18)F-FDG uptake in secondary lymphoid organs. Conclusion: These findings reveal hitherto unknown functional links between STING signaling and immunometabolism and suggest that (18)F-FDG PET may provide a widely applicable approach toward measuring the pharmacodynamic effects of systemic STING agonists at a whole-body level and guiding their clinical development. |
| Databáze: | OpenAIRE |
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