Oncotarget

Research Papers:

Intratumoral immunotherapy with STING agonist, ADU-S100, induces CD8+ T-cell mediated anti-tumor immunity in an esophageal adenocarcinoma model

Ali H. Zaidi _, Ronan J. Kelly, Anastasia Gorbunova, Ashten N. Omstead, Madison S. Salvitti, Ping Zheng, Juliann E. Kosovec, Soyoung Lee, Shahin Ayazi, Laila Babar, Gene G. Finley, Ajay Goel and Blair A. Jobe

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Abstract

Ali H. Zaidi1,*, Ronan J. Kelly2,*, Anastasia Gorbunova1, Ashten N. Omstead1, Madison S. Salvitti1, Ping Zheng1, Juliann E. Kosovec1, Soyoung Lee3, Shahin Ayazi1, Laila Babar1, Gene G. Finley1, Ajay Goel4 and Blair A. Jobe1

1 Esophageal and Lung Institute, Allegheny Health Network, Pittsburgh, PA, USA

2 Department of Hematology and Oncology, Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA

3 Department of Radiation Oncology, Allegheny Health Network, Pittsburgh, PA, USA

4 Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Monrovia, CA, USA

* Co-first authors and contributed equally to this work

Correspondence to:

Ali H. Zaidi,email: Ali.zaidi@ahn.org

Keywords: esophageal adenocarcinoma; STING; PD-L1; CD8+ T-cells; IFNβ

Received: November 20, 2020     Accepted: January 26, 2021     Published: February 16, 2021

Copyright: © 2021 Zaidi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

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.


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