Au naturale: use of biologically derived cyclic di-nucleotides for cancer immunotherapy

Cyclic di-nucleotides (CDNs) are widespread second messenger signalling molecules that regulate fundamental biological processes across the tree of life. These molecules are also potent modulators of the immune system, inducing a Type I interferon response upon binding to the eukaryotic receptor STING. Such a response in tumours induces potent immune anti-cancer responses and thus CDNs are being developed as a novel cancer immunotherapy. In this review, I will highlight the use, challenges and advantages of using naturally occurring CDNs to treat cancer.

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Development of Small-Molecule STING Activators for Cancer Immunotherapy

Biomedicines ◽

10.3390/biomedicines10010033 ◽

2021 ◽

Vol 10 (1) ◽

pp. 33

Author(s):

Hee Ra Jung ◽

Seongman Jo ◽

Min Jae Jeon ◽

Hyelim Lee ◽

Yeonjeong Chu ◽

...

Keyword(s):

Cancer Immunotherapy ◽

Cyclic Gmp ◽

Therapeutic Potential ◽

Interferon Response ◽

Type I ◽

Anti Cancer ◽

Cancer Agent ◽

Sting Pathway

In cancer immunotherapy, the cyclic GMP–AMP synthase–stimulator of interferon genes (STING) pathway is an attractive target for switching the tumor immunophenotype from ‘cold’ to ‘hot’ through the activation of the type I interferon response. To develop a new chemical entity for STING activator to improve cyclic GMP-AMP (cGAMP)-induced innate immune response, we identified KAS-08 via the structural modification of DW2282, which was previously reported as an anti-cancer agent with an unknown mechanism. Further investigation revealed that direct STING binding or the enhanced phosphorylation of STING and downstream effectors were responsible for DW2282-or KAS-08-mediated STING activity. Furthermore, KAS-08 was validated as an effective STING pathway activator in vitro and in vivo. The synergistic effect of cGAMP-mediated immunity and efficient anti-cancer effects successfully demonstrated the therapeutic potential of KAS-08 for combination therapy in cancer treatment.

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Viperin binds STING and enhances the type-I interferon response following dsDNA detection

10.1101/493098 ◽

2018 ◽

Cited By ~ 3

Author(s):

Keaton M. Crosse ◽

Ebony A. Monson ◽

Arti B. Dumbrepatil ◽

Monique Smith ◽

Yeu-Yang Tseng ◽

...

Keyword(s):

Type I Interferon ◽

Innate Immune ◽

Signalling Pathway ◽

Interferon Response ◽

Type I ◽

Viral Pathogens ◽

Radical Sam ◽

Signalling Molecules ◽

Inducible Protein ◽

Interferon Inducible Protein

AbstractViperin is an interferon-inducible protein that is pivotal for eliciting an effective immune response against an array of diverse viral pathogens. Here we describe a mechanism of viperin’s broad antiviral activity by demonstrating the protein’s ability to synergistically enhance the innate immune dsDNA signalling pathway to limit viral infection. Viperin co-localised with the key signalling molecules of the innate immune dsDNA sensing pathway, STING and TBK1; binding directly to STING and inducing enhanced K63-linked polyubiquitination of TBK1. Subsequent analysis identified viperin’s necessity to bind the cytosolic iron-sulphur assembly component 2A, to prolong its enhancement of the type-I interferon response to aberrant dsDNA. Here we show that viperin facilitates the formation of a signalling enhanceosome, to coordinate efficient signal transduction following activation of the dsDNA signalling pathway; which results in an enhanced antiviral state. We also provide evidence for viperin’s radical SAM enzymatic activity to self-limit its immunomodulatory functions. This data further defines viperin’s role as a positive regulator of innate immune signalling, offering a mechanism of viperin’s broad antiviral capacity.

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Faculty Opinions recommendation of Lymphotoxin-mediated crosstalk between B cells and splenic stroma promotes the initial type I interferon response to cytomegalovirus.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1104493.560531 ◽

2008 ◽

Author(s):

Ann Hill

Keyword(s):

B Cells ◽

Type I Interferon ◽

Interferon Response ◽

Type I

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Faculty Opinions recommendation of USP15 regulates type I interferon response and is required for pathogenesis of neuroinflammation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726829800.793527398 ◽

2017 ◽

Author(s):

Benedict Michael ◽

Mark Ellul

Keyword(s):

Type I Interferon ◽

Interferon Response ◽

Type I

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Viral Invasion and Type I Interferon Response Characterize the Immunophenotypes during COVID-19 Infection

SSRN Electronic Journal ◽

10.2139/ssrn.3555695 ◽

2020 ◽

Cited By ~ 8

Author(s):

Lai Wei ◽

Siqi Ming ◽

Bin Zou ◽

Yongjian Wu ◽

Zhongsi Hong ◽

...

Keyword(s):

Type I Interferon ◽

Interferon Response ◽

Type I

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Positive natural selection in primate genes of the type I interferon response

BMC Ecology and Evolution ◽

10.1186/s12862-021-01783-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Elena N. Judd ◽

Alison R. Gilchrist ◽

Nicholas R. Meyerson ◽

Sara L. Sawyer

Keyword(s):

Natural Selection ◽

Positive Selection ◽

Type I Interferon ◽

Interferon Response ◽

Type I ◽

Sequence Alignments ◽

Multiple Sequence ◽

Multiple Sequence Alignments ◽

Interferon Stimulated Genes ◽

Interferon Induction

Abstract Background The Type I interferon response is an important first-line defense against viruses. In turn, viruses antagonize (i.e., degrade, mis-localize, etc.) many proteins in interferon pathways. Thus, hosts and viruses are locked in an evolutionary arms race for dominance of the Type I interferon pathway. As a result, many genes in interferon pathways have experienced positive natural selection in favor of new allelic forms that can better recognize viruses or escape viral antagonists. Here, we performed a holistic analysis of selective pressures acting on genes in the Type I interferon family. We initially hypothesized that the genes responsible for inducing the production of interferon would be antagonized more heavily by viruses than genes that are turned on as a result of interferon. Our logic was that viruses would have greater effect if they worked upstream of the production of interferon molecules because, once interferon is produced, hundreds of interferon-stimulated proteins would activate and the virus would need to counteract them one-by-one. Results We curated multiple sequence alignments of primate orthologs for 131 genes active in interferon production and signaling (herein, “induction” genes), 100 interferon-stimulated genes, and 100 randomly chosen genes. We analyzed each multiple sequence alignment for the signatures of recurrent positive selection. Counter to our hypothesis, we found the interferon-stimulated genes, and not interferon induction genes, are evolving significantly more rapidly than a random set of genes. Interferon induction genes evolve in a way that is indistinguishable from a matched set of random genes (22% and 18% of genes bear signatures of positive selection, respectively). In contrast, interferon-stimulated genes evolve differently, with 33% of genes evolving under positive selection and containing a significantly higher fraction of codons that have experienced selection for recurrent replacement of the encoded amino acid. Conclusion Viruses may antagonize individual products of the interferon response more often than trying to neutralize the system altogether.

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