STING-induced blood-brain barrier opening in combination with radiation therapy potentiates anti-glioma immune and therapeutic activity monitored with [18F]-FLT PET

ABSTRACT: Radiation therapy (RT) is the standard of care for glioblastoma but is not curative. Triggering the cGAS/STING pathway with potent agonists such as 8803 exerts marked activity across high-grade glioma preclinical models through the induction of anti-tumor immune responses. To determine if the combination of 8803 with radiation therapy (RT) warrants consideration in the upfront treatment setting and to clarify the underlying mechanisms of therapeutic activity, C57BL/6 mice harboring intracerebral CT-2A or QPP8v high-grade gliomas were treated with fractionated RT (2 Gy daily for 5 days), intratumoral 8803, or both regimens. The treatment with 8803 with RT resulted in 80% long-term and undefined median survival (MS) relative to monotherapy (control MS: 25; 8803 MS: 36; RT MS: 38 days) in the high-grade CT-2A glioma model (combination vs. control p<0.0001), but not in the radiation-resistant QPP8v model. CRISPR gene editing was used to knock out (KO) the STING pathway in CT-2A glioma tumor cells to model the epigenetic silencing of STING expression in human glioblastoma. In this setting, the combinatorial therapeutic effect has been maintained, highlighting that the direct contribution of immune system in mediating survival benefit. The 8803-mediated STING activation was visualized longitudinally using [18F]-FLT uptake. In CT-2A-bearing mice, maximum peak of the [18F]-FLT uptake was observed at 72-96 hours after 8803 administration. Sc-RNA sequencing of the CT-2A glioma during the therapeutic window identified a nitric oxide synthase gene signature in the Inflam-TAM(2) population associated with combinatorial efficacy. However, the therapeutic effect of 8803, RT, or the combination of RT + 8803 was not ablated in the NOS2 background mice, indicating that this pathway is not a major contributor to therapeutic activity. scRNA sequencing revealed that 8803 treatment reprograms the blood-brain barrier (BBB) through changes in the PECAM and CD147 pathways in the endothelial cell. A single intracranial injection of 8803, but not RT monotherapy, in non-tumor bearing C57BL/6J mice, induced diffuse bi-hemispheric blood-brain barrier (BBB) opening, shown by fluorescent imaging up to 24 hours, but not in STING KO background mice. In summary, a 8803, combined with RT, triggers distinctive anti-glioma immune reactivity, facilitates brain immune infiltration through the opening of the BBB, and warrants consideration for clinical trials in the up-front setting for glioblastoma that can be monitored with [18F]-FLT PET imaging.

ORGANISM(S): Mus musculus

PROVIDER: GSE305400 | GEO | 2025/12/03

REPOSITORIES: GEO