Stimulator of interferon genes, or STING, helps regulate immune activation. Thus, drugs that activate STING are being tested as a form of cancer immunotherapy and for treating certain infections. Findings from this study reveal previously unknown functional links between STING signaling and immunometabolism. They also suggest that positron emission tomography (PET) imaging could provide a widely accessible approach to measure the pharmacodynamic effects of using STING-activating drugs.
Oral and IV administration of STING-activating drugs induce potent anti-tumor responses in mouse models of cancer, suggesting this as a possible strategy for human therapy. Until now, however, researchers have had no way to determine the extent, duration, and location of immune activation. This study, led by researchers from UCLA Jonsson Comprehensive Cancer Center, investigated whether systemic STING activation causes metabolic changes in immune cells that can be visualized by PET imaging.
Lab mice were treated with systemic STING agonists and later imaged with PET scans using standard fluorodeoxyglucose (FDG) radiotracing. Immune cells from the spleen were analyzed by RNA sequencing and flow cytometry. The amount of tracer in B and T lymphocytes was measured. In mice bearing prostate cancer or pancreatic cancer tumors, the effects of STING agonist treatment on tracer uptake, levels of T-lymphocyte activation, and tumor growth were evaluated.
Systemic delivery of STING-activating drugs in mice significantly increased the uptake of PET tracers in the brain. Analyzes of immune cells indicated an increase in tracer in both T and B lymphocytes correlated with the induction of markers for immune cell activation. In tumor-bearing mice, STING agonist administration significantly delayed tumor growth and increased radiotracer uptake in secondary lymphoid glands. In addition to identifying previously unknown functional links between STING signaling and immunometabolism, the study suggests that readily available PET scanning enables whole-body analysis of the effects of systemic STING-activating therapy in humans. This may potentially provide a diagnostic tool that guides the clinical development of this treatment approach.
“A new generation of STING agonists has broadened the available routes of administration to include systemic immune activation and thus is moving rapidly into the clinical setting of cancer immunotherapy,” said co-first co-author Hailey Lee, a graduate student in the lab. from Dr. Caius Radu, a professor in the Molecular and Medical Pharmacology and Surgery Departments at UCLA and member of the UCLA Jonsson Comprehensive Cancer Center.
Radu, the senior author of the article, said: “Given that overstimulation of the immune system can lead to potential toxic side effects for STING agonists, important questions remain about optimizing the correct dose and treatment schedule for individual patients. Our recent investigation into the identification of a clinically applicable biomarker highlights PET as a readout for measuring STING agonist-induced immune activation in both the preclinical and clinical settings.”
Co-first author Thuc Le, an adjunct professor of molecular and medical pharmacology at UCLA, added: “Such imaging tools can guide the dosing and scheduling of STING agonists to minimize the risk of immune overstimulation while still maintaining therapeutic efficacy. We hope that our findings will have an impact on the clinical application of STING agonists.”
Co-first authors Thuc Le and Hailey Lee are UCLA researchers, as are Evan Abt, Khalid Rashid, Amanda Creech, Liu Wei, Amanda Labora, Charlotte Chan, Eric Sanchez, Daniel Karin, Luyi Li, Nanping Wu, Christine Mona, Giuseppe Carlucci , Willy Hugo, Ting-Ting Wu, Timothy Donahue, Johannes Czernin, and corresponding author Caius Radu. Keke Liang is with China Medical University in Shenyang, China. Jing Cui is with Huazhong University of Science and Technology in Hubei, China. Arthur Cho is with Yonsei University College of Medicine in Seoul, South Korea. Kriti Kriti is with Elucidata Corp. in Cambridge, Massachusetts.
The, TM, and others. (2022) 18F-FDG PET visualizes systemic STING agonist-induced lymphocyte activation in preclinical models. Journal of Nuclear Medicine. doi.org/10.2967/jnumed.122.264121.
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