STING-driven interferon signaling triggers metabolic alterations in pancreas cancer cells visualized by [ 18 F]FLT PET imaging.

Type I interferons (IFNs) are critical effectors of emerging cancer immunotherapies designed to activate pattern recognition receptors (PRRs). A challenge in the clinical translation of these agents is the lack of noninvasive pharmacodynamic biomarkers that indicate increased intratumoral IFN signaling following PRR activation. Positron emission tomography (PET) imaging enables the visualization of tissue metabolic activity, but whether IFN signaling-induced alterations in tumor cell metabolism can be detected using PET has not been investigated. We found that IFN signaling augments pancreatic ductal adenocarcinoma (PDAC) cell nucleotide metabolism via transcriptional induction of metabolism-associated genes including thymidine phosphorylase (TYMP). TYMP catalyzes the first step in the catabolism of thymidine, which competitively inhibits intratumoral accumulation of the nucleoside analog PET probe 3'-deoxy-3'-[ ¹⁸ F]fluorothymidine ([ ¹⁸ F]FLT). Accordingly, IFN treatment up-regulates cancer cell [ ¹⁸ F]FLT uptake in the presence of thymidine, and this effect is dependent upon TYMP expression. In vivo, genetic activation of stimulator of interferon genes (STING), a PRR highly expressed in PDAC, enhances the [ ¹⁸ F]FLT avidity of xenograft tumors. Additionally, small molecule STING agonists trigger IFN signaling-dependent TYMP expression in PDAC cells and increase tumor [ ¹⁸ F]FLT uptake in vivo following systemic treatment. These findings indicate that [ ¹⁸ F]FLT accumulation in tumors is sensitive to IFN signaling and that [ ¹⁸ F]FLT PET may serve as a pharmacodynamic biomarker for STING agonist-based therapies in PDAC and possibly other malignancies characterized by elevated STING expression.
Competing Interests: Competing interest statement: C.G.R. and J. Czernin are cofounders of Sofie Biosciences and the Trethera Corporation. They and the University of California hold equity in Sofie Biosciences and the Trethera Corporation. T.R.D. is an executive board member and holds equity in the Trethera Corporation.