Background: Esophageal adenocarcinoma (EAC) is a deadly disease with limited treatment options. STING is a transmembrane protein that activates transcription of interferon genes, resulting in stimulation of APCs and enhanced CD8+ T-cell infiltration. The present study evaluates STING agonists, alone and in combination with radiation to determine durable anticancer activity in solid tumors.

Materials and Methods: Esophagojejunostomy was performed on rats to induce reflux leading to the development of EAC. At 32 weeks post operatively, rats received intratumorally either 50 μg STING (ADU-S100) or placebo (PBS),+/–16Gy radiation. Drug activity was evaluated by pre-and post-treatment MRI, histology, immunofluorescence and RT-PCR.

Results: Mean MRI tumor volume decreased by 30.1% and 50.8% in ADU-S100 and ADU-S100+ radiation animals and increased by 76.7% and 152.4% in placebo and placebo+ radiation animals, respectively (P< 0.0001). Downstream gene expression, pre-to on-and post-treatment, demonstrated significant upregulation of IFNβ, TNFα, IL-6, and CCL-2 in the treatment groups vs. placebo. On-or post-treatment, radiation alone, ADU-S100 alone, and ADU-S100+ radiation groups demonstrated enhanced PD-LI expression, induced by upregulation of CD8+ T-cells (p< 0.01).

Conclusions: ADU-S100+/–radiation exhibits potent antitumor activity and a promising immunomodulatory profile in a de novo EAC.