STING Activators As Cancer Therapeutics

The potential to harness an individual’s immune system to treat cancer has revolutionized the oncology field. Coined immunotherapy, this umbrella term describes several types of treatment, including immune checkpoint inhibitors, immune system modulators, and adoptive cell therapies. Each triggers the immune system in a different way to fight cancer.

 

One approach currently being explored involves stimulating innate immune response pathways. For example, the STimulator of InterferoN Genes (STING) pathway, which is known to play a critical role in innate immunity in response to viral and bacterial DNA, has also been shown to promote anti-tumor immune responses.

 

Researchers are therefore exploring the development of synthetic STING activators as potential cancer therapeutics.

 

Our scientists have developed assays to examine several pathways, including: STING binding, phosphorylation and downstream signaling proteins; cytokine secretion, including IFN-β; and cell and protein analysis tools to characterize cancer biology. Additionally, our GoInVivo™ reagents focus on targeting immune checkpoints which can be leveraged by tumor cells to shut down the immune response.

 

Our newly released LEGENDplex™ Human Angiogenesis Panel 1 (10-plex) can be used to detect pivotal factors and cytokines involved in cell adhesion and angiogenesis - the process of new blood vessel creation that promotes tumor growth, progression, and metastasis.

 

Exploring the STING Pathway

 

STING is a transmembrane protein which is located in the endoplasmic reticulum (ER) and is widely expressed in both immune and non-immune cells. Activation of the STING pathway occurs when cyclic GMP–AMP synthase (cGAS) recognizes and binds to double-stranded DNA (dsDNA) in the cytosol of the cell. This binding results in the activation of cGAS and subsequent synthesis of the cyclic dinucleotide (CDN) STING ligand, 2′3′ cyclic GMP–AMP (cGAMP). Binding of cGAMP to STING dimers activates downstream transcription factors STAT6 and IRF3 and leads to production and transcription of host defense genes, including type I interferons (IFNs) such as IFN-β and other pro-inflammatory cytokines.

 

While viral and bacterial dsDNA is known to activate STING-dependent immune signaling, research shows that self-DNA from tumors can also stimulate the STING pathway and several CDN agonists of STING are currently being assessed in human clinical trials of various malignancies. However, early single-agent human results have not been as promising as predicted by preclinical models, with poor cytosolic delivery, tumor extravasation, and non-selective delivery being some of the limitations observed.

 

A team of scientists at Codiak Biosciences recently explored the potential of exoSTING, an engineered extracellular vesicle (EV) exogenously loaded with CDN, to enhance the delivery of STING agonists. The work was prompted by the knowledge that EVs are natural mediators of signaling between cancer cells and tumor resident antigen presenting cells (APCs), with some activating a type I IFN response via the STING pathway.

 

Writing in Communications Biology1, the researchers said, “Our goal was to address the limitations of CDN by using EVs as a delivery vehicle that would specifically activate the STING pathway in APCs while avoiding T cell ablation.”

 

exoSTING Promotes Tumor Immune Surveillance

 

The research group utilized numerous tools and techniques to explore the in vitro and in vivo potential of exoSTING. These included PerkinElmer’s AlphaLISA® IFN-β assay kit, our recombinant human M-CSF, as well as numerous BioLegend antibodies for flow cytometry, LEGENDplex™ flow cytometry-based multiplexing, and in vivo depletion and blockade of immune checkpoint molecules.

 

Over the course of their in-depth analysis, the researchers found that exoSTING enhanced the potency of CDN and preferentially activated APCs in the tumor microenvironment. They also found that exoSTING was retained within the tumor following intratumoral injection, enhanced local Th1 responses and recruitment of CD8+ T cells, and generated systemic anti-tumor immunity.

 

Finally, exoSTING administered at therapeutically active doses did not induce systemic inflammatory cytokines, resulting in an enhanced therapeutic window. “The improved potency and wider therapeutic window of exoSTING should enable optimized dosing strategies in the clinic through precise delivery of CDNs,” said the researchers.

 

ExoSTING represents a novel strategy to harness and improve upon natural immune surveillance in the TME and may overcome many of the observed limitations with dose selection of free CDNs, which are currently in the early stages of clinical development, the team concluded.

 

Advancing Future Research

 

In the hunt for the next breakthrough cancer immunotherapy, PerkinElmer and BioLegend are committed to providing tools and reagents for scientists to explore the complexities of cancer biology with fast and accurate results.

 

 

This post was originally published by PerkinElmer2.

 

 

References

  1. Jang, S.C., Economides, K.D., Moniz, R.J. et al. ExoSTING, an extracellular vesicle loaded with STING agonists, promotes tumor immune surveillance. Commun Biol 4, 497 (2021). doi:10.1038/s42003-021-02004-5. PubMed.
  2. Novel therapeutic candidate puts the sting back into immunotherapy. PerkinElmer Blog. (2022).
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