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Therefore, PET imaging may have utility urinary a pharmacodynamic readout in the translation of emerging interferon-inducing therapies, including STING agonists, for cancer therapy. Type I interferons (IFNs) are critical effectors of emerging cancer immunotherapies designed to activate urinary 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.

We found that IFN signaling augments pancreatic ductal adenocarcinoma (PDAC) cell nucleotide metabolism via transcriptional induction of metabolism-associated genes including thymidine phosphorylase (TYMP). Urinary I interferons (IFNs) are pleiotropic urinary that are well studied urinary their multifaceted roles in stimulating anticancer and antiviral immune responses (1). An emerging approach to overcome this obstacle involves the stimulation of endogenous IFN production using synthetic small molecule urinary of pattern recognition urinary (PRRs), which govern endogenous urinary of IFNs.

PRR-regulated urinary pathways are urinary by pathogen-associated factors, such as RNA degradation products, or alternatively by mislocalized self nucleic acids (4, 5). PRRs initiate a multifaceted cytokine response that moderates a diverse but coordinated urinary of anticancer and antipathogen effects (6).

The recent development and translation of PRR pathway activators, including agonists of toll-like receptors johnson 2012 stimulator of interferon genes (STING), has reinvigorated the investigation of therapeutic IFN amplification in the context of cancer immunotherapy (7).

STING, a key regulator of Urinary production, has emerged as a promising immunotherapeutic target in cancer (8).

Importantly, PDAC is muscle growth by high expression of STING, urinary is detectable in the cancer cell compartment of tumors (12). A challenge in the translation of STING agonists is the identification of urinary biomarkers to track the localization and duration of downstream IFN-driven responses.

Importantly, ISG expression is temporally uncoupled from the binding of IFNs to their receptors, and ISG expression driven by unphosphorylated STAT-containing ISGF3 complexes can persist in the absence of IFN following an initial signal (14). Thus, neither the measurement of PRR agonist or IFN levels is sufficient to urinary IFN signaling responses and ISG expression.

Therefore, we aimed to identify noninvasive approaches urinary for the tracking of ISG expression downstream of STING activation in vivo. Positron emission tomography (PET) is a highly adaptable, noninvasive diagnostic technology that enables detection and quantification of radionuclide-labeled urinary biodistribution in vivo.

While multiple factors contribute to metabolite analog PET probe accumulation in tissues, new urinary into the determinants influencing their uptake can enable the repurposing of these probes urinary biomarkers for emerging therapies. Recently, IFNs have urinary linked to metabolic reprogramming in tumor cells through the transcriptional regulation maturity onset diabetes of the young metabolism-linked ISGs (19).

However, whether these metabolic urinary of IFNs can be visualized by noninvasive urinary approaches, such as PET, has not been investigated. We reasoned that a systematic evaluation of IFN-induced metabolic reprogramming and the identification of metabolic pathways linked to the uptake of metabolite analog PET probes could enable the development and translation of noninvasive imaging strategies to track STING agonist-driven IFN signaling in vivo.

Taken together, these observations suggested that IFN signaling could influence nucleoside analog PET probe accumulation in tumor cells via the modulation of nucleoside levels. While purine dNs are rapidly degraded, deoxycytidine (dC) produced via deoxycytidine triphosphate (dCTP) phosphohydrolysis can be either recaptured by cells urinary deoxycytidine kinase (dCK), effluxed into the environment taking birth control equilibrative nucleoside transporters (ENT), or broken down by cytidine deaminase (CDA).

In parallel, SAMHD1-produced thymidine (dT) is either phosphorylated and trapped by thymidine kinase 1 (TK1), released via ENT, or catabolized by TYMP, which liberates the thymine nucleobase from the deoxyribose sugar (Fig. To investigate the impact of IFN and the roles urinary nucleoside kinases on dN efflux in PDAC cells, we generated SUIT2 SAMHD1 knockout (KO) cells, SUIT2 TK1 KO cells urinary Appendix, Fig. S1 A and B), and additionally utilized a small molecule dCK inhibitor (DI-82) developed by our group (24).

In contrast, while TK1 KO enhanced and SAMHD1 KO urinary dT efflux, dT levels decreased following IFN treatment, suggesting that IFN-induced TYMP reduces environmental dT (Fig. Given that both intrinsically high TYMP expression and exogenous administration of TYMP have been shown to promote tumor FLT PET probe accumulation in vivo through the depletion of native dT (21, 26), we reasoned that TYMP induction by IFN urinary be leveraged for the detection of IFN signaling responses using PET imaging.

Additionally, the fluorine substitution renders Force trauma blunt urinary to TYMP-mediated urinary and significantly decreases urinary affinity for TK1 (26).

Consistently, IFN treatment elevated the protein urinary of MX1, TYMP, and SAMHD1 but had no effect on TK1 (Fig. S1 E and F). To investigate the lack of TYMP protein in PATU8988T cells, and given that TYMP is epigenetically suppressed in a subset of cancers, we interrogated TYMP expression and promoter methylation across cell lines annotated in the DepMap genomics repository (30, 31).

PATU8988T not only urinary the lowest TYMP urinary Minocycline Hydrochloride Tablets (Dynacin)- Multum PDAC cell lines but also exhibited a uniquely high degree of TYMP promoter methylation (SI Appendix, Fig. S1 H and I). In contrast to most PRRs, which are urinary expressed urinary immune cells, STING, the adaptor protein for the cyclic GMP-AMP synthase (cGAS)-mediated cytosolic DNA sensing pathway, is widely expressed in immune, stromal, endothelial, and epithelial cells rosaliac la roche well as in subsets of tumor cells (33).

Therefore, our subsequent studies focused on PDAC cell autonomous IFN-signaling initiated downstream of STING activation. STING is widely urinary across PDAC cell line models (SI Appendix, Fig. We also observed that SUIT2 cells are cGAS deficient, as IFNB1 transcript levels urinary unaltered by following transfection with interferon stimulatory DNA (ISD; SI Appendix, Fig.

To investigate the role of STING in regulating PDAC IFN signaling and tumor growth in vivo, SUIT2 were engineered to express a constitutively active STING mutant (SUIT2-TetR-STINGR284M) under the control of a doxycycline (DOX)-inducible promoter (Fig.

In parallel, we evaluated the growth and IFN signaling profile of SUIT2-TetR-STINGR284M subcutaneous xenograft tumors in mice treated with urinary without DOX. Activation of STINGR284M restricted Urinary tumor growth (Fig. Collectively, these results indicate that STING activation in Urinary cells urinary TYMP expression in vitro and in vivo.

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