The Barber Lab team at the OSUCCC – James, led by cancer research specialist and Principal Investigator Glen Barber, PhD, FRS, focuses on studying mechanisms of host defense against microbes and cancer.
Through these studies, the world-renowned research specialists in the Barber Lab have discovered how cells in the body recognize microbial infection and precancerous cells to trigger host-defense responses.
This process is controlled by cellular sensors that recognize microbe-specific molecules, which elicit an innate immune signaling cascade. That leads to the transcription of key genes such as type I interferon (IFN) and cytokines that stimulate adaptive immunity. While this is essential for host-defense countermeasures, such cellular innate immune signaling pathways can also cause inflammation if overstimulated. Therefore, innate immune signaling processes are carefully controlled to avoid chronic cytokine production.
Innate immune signaling is also essential for effectively generating anti-tumor adaptive immunity. Understanding these mechanisms has provided considerable insight into cancer immunobiology and has subsequently led to developing novel therapeutics that treat a variety of cancer-related diseases.
Mission
At the OSUCCC – James, the Barber Lab research scientists’ mission is to study mechanisms of host defense against microbes and cancer to further insights into pathogenesis and to continue to develop novel therapeutics that treat a variety of infectious, inflammatory and cancer-related diseases. These nationally and internationally recognized experts focus their research in three critical areas:
Infectious Disease
Innate Immune Signaling & Infectious Disease
The Toll-Like Receptor (TLR) and Rig-I-Like Receptor (RLR) cellular pathways play key roles in recognizing microbial infection – predominantly RNA viruses and bacteria – to trigger innate immune signaling and the generation of type I IFN.
In 2008, Glen Barber, PhD, FRS and his research team reported their discovery of an important cellular protein, dubbed STING (stimulator of interferon genes), which controls a new innate immune signaling pathway. This research and discovery led to elucidating how DNA-based microbes trigger host-defense countermeasures (Ishikawa and Barber, Nature 2008; Ishikawa, Ma and Barber Nature 2009).
Here's how it works: the cytosol is supposed to be devoid of dsDNA species. If dsDNA species are present, it likely either comes from an invading microbe, from damaged mitochondria or from the nucleus of a DNA-damaged cell. In these circumstances, STING signaling activates cytokine production, which attracts the immune system to the problematic region.
STING is a cytosolic sensor for cyclic dinucleotides (CDNs) such as GMP-GMP and GMP-AMP. CDNs are generated either by intracellular bacteria following infection or by a cellular synthase called cGAS, which generates CDNs following interaction with cytosolic microbial or self-dsDNA species.
These studies and discoveries by the Barber Lab team of research experts and others have demonstrated that transient STING activity is essential for host-defense countermeasures following infection by DNA viruses, bacteria and parasites (Ishikawa and Barber, Nature 2008; Ishikawa et al., Nature 2009; Barber G.N., Nature Immunology Reviews, 2015).
Inflammation
Autoinflammatory Disease and Innate Immunity
Evidence indicates that patients suffering from autoinflammatory diseases such as systemic lupus erythematosus (SLE) commonly produce antibodies to their own DNA (anti-nuclear antibodies, or ANA).
The Barber Lab researchers postulated that DNA-activated innate immune pathways may play a role in manifesting such disorders.
Subsequent research by these experts and others has now demonstrated that chronic STING signaling can indeed be a cause inflammatory disease (Ahn et al., PNAS, 2012). In large part, this happens because of genetic defects in Dnase, which normally ensure that any genomic DNA leaking into the cytoplasm is rapidly degraded prior to activating STING signaling.
For example, patients with Aicardi-Goutieres Syndrome (AGS), a severe form of SLE, exhibit defects in DNase III, which causes chronic STING signaling manifested by undigested cytosolic self-DNA (Gall et al., Immunity 2012; Ahn et al., J. Immunol, 2014). These observations subsequently raised the possibility that STING signaling could be involved in a wide variety of alternate inflammatory malaise (Konno et al., CELL Reports 2018). It has now been reported that inflammation can be caused by mutations in the STING gene itself, which causes the molecule to be permanently active (STING-associated vasculopathy with onset in infancy- SAVI).
Evidence also suggests that STING in macrophages interacts with commensal bacteria to maintain gut immune homeostasis (Ahn et al., Cell Reports 2017). Thus, disruption of STING signaling could play a key role in facilitating inflammatory bowel disease (IBD). Chronic STING signaling has now been shown to be a potential cause of neurodegenerative diseases and a variety of other autoinflammatory malaises.
Aside from providing significant new mechanistic insight into self-DNA manifested diseases, such research has opened up the possibility that drugs that could suppress STING signaling may be beneficial for treating a wide variety of inflammatory disorders.
Cancer
STING Signaling and Cancer
The Barber Lab scientists’ research indicates that DNA from dying tumor cells plays an important role in triggering extrinsic STING signaling in engulfing phagocytes (antigen presenting cells, or APCs). Extrinsic STING-dependent cytokine production in APCs is essential for the efficient cross presentation of tumor cell antigens and generating anti-tumor T-cell responses.
STING-deficient mice do not efficiently generate anti-tumor T-cell responses (Woo et al., Immunity 2014). Tumor cells, however, are notoriously non-immunogenic because their genomic DNA inefficiently activates STING in APCs, following phagocytosis. In fact, tumor cells mimic normal apoptotic cells following phagocytic engulfment and do not generate a robust immune response. This is because DNases in apoptotic cells (DNase III) and phagocytes (DNase II) ensure that all the dead cells’ DNA is degraded to avoid STING-dependent inflammation (Ahn et al., PNAS 2012).
This knowledge has enabled the Barber Lab research experts to develop new therapeutic approaches to overcome these obstacles and to convert non-immunogenic tumor cells (cold) into highly immunogenic (hot) by using STING agonists – referred to as STAVs- STING activators (Ahn et al., Cancer Cell, 2018). His laboratory has now developed a number of novel clinical trials, based on his research, to treat malignant disease.
A number of studies have found that CDN’s induce powerful anti-tumor activity through stimulation of STING in the tumor microenvironment. This research has led to CDN-like drugs being evaluated in the clinic as immunotherapeutic anti-cancer agents.
Inflammation can also enhance the development of tumors. As an extension of the Barber Lab research team’s work, these experts demonstrated that chronic STING signaling can fuel certain inflammation-driven cancers (Ahn et al., Nature Communications 2014). For example, STING-deficient mice are significantly resistant to tumor development induced by chronic exposure to carcinogens. (Barber G.N. Nature Reviews Immunology).
Current research and studies
STING Signaling
- Contributions to Unraveling Mechanisms of Innate Immune Signaling
- Discovery of the STING, Cytosolic DNA Activated Innate Immune Pathway
- Viruses as Therapeutics for Cancer
Who we are and how we do it
Glen Barber, PhD, FRS, is a professor in the Department of Surgery/Division of Oncology, the Associate Director of Entrepreneurship and Innovation with the OSUCCC – James and the Director of the Center for Innate Immunity and Inflammation for the Pelotonia Institute of Immuno-Oncology.
For more information on the Barber Lab team, collaborations, opportunities and lab-specific inquiries, please contact Glen.Barber@osumc.edu.