Intratumoral immunotherapy with STING agonist, ADU-S100, induces CD8+ T-cell mediated anti-tumor immunity in an esophageal adenocarcinoma model
| Autor: | Juliann E. Kosovec, Laila Babar, Shahin Ayazi, Gene Grant Finley, Ali H. Zaidi, Soyoung Lee, Blair A. Jobe, Ashten N. Omstead, Madison Salvitti, Ronan J. Kelly, Ping Zheng, Ajay Goel, Anastasia Gorbunova |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Agonist PD-L1 esophageal adenocarcinoma medicine.drug_class medicine.medical_treatment 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Interferon medicine biology business.industry CD8+ T-cells Immunotherapy Sting 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research biology.protein Tumor necrosis factor alpha business CD8 IFNβ medicine.drug Research Paper STING |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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