Considerations for the delivery of STING ligands in cancer immunotherapy

Petrovic, Marija; Borchard, Gerrit; Jordan, Olivier

doi:10.1016/j.jconrel.2021.09.033

Cited by 27 publications

(24 citation statements)

References 110 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This would be an appealing possibility, as direct STING agonists to date have either been limited by toxicity when given systemically or lacked systemic therapeutic effects in metastatic disease when administered intratumorally to a single lesion (72). Additionally, activity of STING agonists has been limited by degradation of cGAMP by extracellular phosphodiesterase and bell-shaped responses, where excessive concentrations of intratumoral STING agonist could lead to T cell apoptosis(73), PD-L1 overexpression on tumor cells and Tregs infiltration, resulting in a negative impact on anti-tumor immunotherapy(74, 75). In addition to this, we are also interested in whether immunotherapy could be synergized with cell damage agents and CD11b-agonists combinations.…”

Section: Discussionmentioning

confidence: 99%

Context-dependent triggering of STING-interferon signaling by CD11b agonists supports anti-tumor immunity in mouse models and human cancer patients

Liu

Hogg

Zuo

et al. 2022

Preprint

View full text Add to dashboard Cite

Chronic activation of inflammatory pathways and suppressed interferon signaling are hallmarks of myeloid cells in immunosuppressive tumors that drive poor responsiveness to conventional and immune therapies. Previous studies have identified agonistic activation of the CD11b integrin as a potential strategy to enhance anti-tumor immunity. However, the mechanisms by which CD11b-agonism reprogram tumor immunity are poorly understood, and this may impair patient selection and identification of effective treatment combinations. Herein we used a combination of in vitro systems, animal models, and samples from first in human clinical trials of the CD11b-agonist GB1275 to identify the mechanism of action of this approach and identify combinations for further testing. We found that CD11b agonism altered tumor-associated macrophage (TAM) phenotypes by simultaneously repressing NFκB/IL1-signaling and activating interferon (IFN) gene expression. Repression of NFκB/IL-1 signaling was due to rapid degradation of p65 protein by the proteosome and was not context dependent. In contrast, CD11b agonism triggered mitochondrial dysfunction to stimulate STING-induced, STAT1-mediated interferon signaling. The magnitude of CD11b agonist induction of STING/IFN signaling was dependent on the tumor microenvironment and was significantly amplified by cytotoxic therapies. Using tissues from phase I clinical trials, we demonstrated that GB1275 treatment activated STING and STAT1 signaling in TAMs in human tumors. Together, these mechanisms allowed macrophages to augment anti-tumor T cell immunity. These studies identified potential mechanism-based therapeutic strategies for CD11b agonist use and identified potential patient populations more likely to benefit from them.

show abstract

Section: Discussionmentioning

confidence: 99%

Context-dependent triggering of STING-interferon signaling by CD11b agonists supports anti-tumor immunity in mouse models and human cancer patients

Liu

Hogg

Zuo

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Suppression of STING activation in pancreatic cancer cells enhanced tumor size by reducing the infiltration of immune cells [ 142 , 143 ]. In mouse model of the breast cancer, cGAMP reduced tumor burden [ 144 ] and liposomal delivery of cGAMP also activated STING in the macrophages [ 145 ]. In syngeneic ovarian cancer (ID8) and colon cancer (CT26), poly (ADPribose) polymerase inhibitors (PARPi) increased IRF3 and STING activity [ 146 ].…”

Section: Cgas-sting Pathway and Pathologiesmentioning

confidence: 99%

Regulation of cGAS Activity and Downstream Signaling

Joshi

Mehta

2022

Cells

View full text Add to dashboard Cite

Cyclic GMP-AMP synthase (cGAS) is a predominant and ubiquitously expressed cytosolic onfirmedDNA sensor that activates innate immune responses by producing a second messenger, cyclic GMP-AMP (cGAMP), and the stimulator of interferon genes (STING). cGAS contains a highly disordered N-terminus, which can sense genomic/chromatin DNA, while the C terminal of cGAS binds dsDNA liberated from various sources, including mitochondria, pathogens, and dead cells. Furthermore, cGAS cellular localization dictates its response to foreign versus self-DNA. Recent evidence has also highlighted the importance of dsDNA-induced post-translational modifications of cGAS in modulating inflammatory responses. This review summarizes and analyzes cGAS activity regulation based on structure, sub-cellular localization, post-translational mechanisms, and Ca2+ signaling. We also discussed the role of cGAS activation in different diseases and clinical outcomes.

show abstract

“…In fact, in addition to CDNs, various STING ligands have been developed and tested in pre-clinical and clinical trials [ 231 ]. The efficient delivery of STING ligands also requires nano-DDS, because they reach the cytosol with difficulty on their own [ 232 ]. We also encapsulated CDNs into a LNP composed of YSK12-C4, an ionizable lipid, and the treatment with the LNP caused elevated levels of serum type I IFN and induced an antitumor effect against lung metastasis [ 193 ].…”

Section: Innate Immunity ( Fig 3 )mentioning

confidence: 99%

Strategies for fighting pandemic virus infections: Integration of virology and drug delivery

Nakamura

Isoda

Sakoda

et al. 2022

Journal of Controlled Release

View full text Add to dashboard Cite

Respiratory viruses have sometimes resulted in worldwide pandemics, with the influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) being major participants. Long-term efforts have made it possible to control the influenza virus, but seasonal influenza continues to take many lives each year, and a pandemic influenza virus sometimes emerges. Although vaccines for coronavirus disease 2019 (COVID-19) have been developed, we are not yet able to coexist with the SARS-CoV-2. To overcome such viruses, it is necessary to obtain knowledge about international surveillance systems, virology, ecology and to determine that immune responses are effective. The information must then be transferred to drugs. Delivery systems would be expected to contribute to the rational development of drugs. In this review, virologist and drug delivery system (DDS) researchers discuss drug delivery strategies, especially the use of lipid-based nanocarriers, for fighting to respiratory virus infections.

show abstract

Considerations for the delivery of STING ligands in cancer immunotherapy

Cited by 27 publications

References 110 publications

Context-dependent triggering of STING-interferon signaling by CD11b agonists supports anti-tumor immunity in mouse models and human cancer patients

Context-dependent triggering of STING-interferon signaling by CD11b agonists supports anti-tumor immunity in mouse models and human cancer patients

Regulation of cGAS Activity and Downstream Signaling

Strategies for fighting pandemic virus infections: Integration of virology and drug delivery

Contact Info

Product

Resources

About