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Characterization of a Novel Compound That Stimulates STING-Mediated Innate Immune Activity in an Allele-Specific Manner
Journal article   Open access   Peer reviewed

Characterization of a Novel Compound That Stimulates STING-Mediated Innate Immune Activity in an Allele-Specific Manner

Jinu Abraham, Sara Botto, Nobuyo Mizuno, Kara Pryke, Bryan Gall, Dylan Boehm, Tina M. Sali, Haihong Jin, Aaron Nilsen, Michael Gough, …
Frontiers in immunology, v 11, pp 1430-1430
08 Jul 2020
DOI: https://doi.org/10.3389/fimmu.2020.01430
PMID: 32733475
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://www.frontiersin.org/articles/10.3389/fimmu.2020.01430/pdfView
Published, Version of Record (VoR) Open
url
https://doi.org/10.3389/fimmu.2020.01430View
Published, Version of Record (VoR) Open

Abstract

Immunology Life Sciences & Biomedicine Science & Technology
The innate immune response to cytosolic DNA involves transcriptional activation of type I interferons (IFN-I) and proinflammatory cytokines. This represents the culmination of intracellular signaling pathways that are initiated by pattern recognition receptors that engage DNA and require the adaptor protein Stimulator of Interferon Genes (STING). These responses lead to the generation of cellular and tissue states that impair microbial replication and facilitate the establishment of long-lived, antigen-specific adaptive immunity. Ultimately this can lead to immune-mediated protection from infection but also to the cytotoxic T cell-mediated clearance of tumor cells. Intriguingly, pharmacologic activation of STING-dependent phenotypes is known to enhance both vaccine-associated immunogenicity and immune-based anti-tumor therapies. Unfortunately, the STING protein exists as multiple variant forms in the human population that exhibit differences in their reactivity to chemical stimuli and in the intensity of molecular signaling they induce. In light of this, STING-targeting drug discovery efforts require an accounting of protein variant-specific activity. Herein we describe a small molecule termed M04 that behaves as a novel agonist of human STING. Importantly, we find that the molecule exhibits a differential ability to activate STING based on the allelic variant examined. Furthermore, while M04 is inactive in mice, expression of human STING in mouse cells rescues reactivity to the compound. Using primary human cells inex vivoassays we were also able to show that M04 is capable of simulating innate responses important for adaptive immune activation such as cytokine secretion, dendritic cell maturation, and T cell cross-priming. Collectively, this work demonstrates the conceivable utility of a novel agonist of human STING both as a research tool for exploring STING biology and as an immune potentiating molecule.

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12 citations in Web of Science
12 citations in Scopus

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Collaboration types
Industry collaboration
Domestic collaboration
Web of Science research areas
Immunology
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