Type I IFN and not TNF, is Essential for Cyclic Di-nucleotide-elicited CTL by a Cytosolic Cross-presentation Pathway

Lirussi, Darío; Ebensen, Thomas; Schulze, Kai; Trittel, Stephanie; Durán, Verónica; Liebich, Ines; Kalinke, Ulrich; Guzmán, Carlos A.

doi:10.1016/j.ebiom.2017.07.016

Cited by 21 publications

(21 citation statements)

References 54 publications

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“…In this study, we demonstrate that the STING ligands 2′3′-cGAMP and 3′3′-cGAMP act as potent adjuvants, enhancing the antigen-driven expansion and functional maturation of effector CD8 + T cells in humans and mice. A mechanistic dissection of these effects in humans revealed that cGAMP elicits a type I IFN response and promotes the maturation of DCs, which have been shown previously to facilitate the cross-priming of antigen-specific CD8 + T cells (20). Moreover, type I IFNs are known to induce the transcription factor T-bet, which is necessary for the development of effector CD8 + T cells (14,16).…”

Section: Discussionmentioning

confidence: 86%

The STING ligand cGAMP potentiates the efficacy of vaccine-induced CD8+ T cells

et al. 2019

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Section: Discussionmentioning

confidence: 86%

The STING ligand cGAMP potentiates the efficacy of vaccine-induced CD8+ T cells

et al. 2019

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“…Fortunately, primary human cells do display responses to M04 such as cytokine secretion, expression of DC maturation markers, and T cell cross-priming that associate with conventional immune activity. Previous work has identified similar phenomena induced by CDN-based agonists (63)(64)(65) as well as dsDNA (66) and diABZI (26). Why some of the DC markers were not induced as expected is unclear and could be related to donor-specific effects such as STING genotype or a skewed set of molecular processes induced in primary tissues by the compound.…”

Section: Discussionmentioning

confidence: 81%

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

et al. 2020

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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 in ex vivo assays 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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“…IFN‐γ plays an important role in inducing innate and adaptive immune effect. The previous studies demonstrated that IFN‐γ upregulated the cells function in tumor immunity . TNF‐α also induced antigen cross‐presentation and T‐cell cross‐priming in cancer immunology and immunotherapy.…”

Section: Discussionmentioning

confidence: 96%

Preparation and anti‐tumor efficiency evaluation of bacterial magnetosome–anti‐4‐1BB antibody complex: Bacterial magnetosome as antibody carriers isolated from Magnetospirillum gryphiswaldense

Tang

Wang

Zhou

et al. 2019

Biotech and App Biochem

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Bacterial magnetosomes (BMs) are used as carriers for antibodies, enzymes, and nucleic acids. This study aimed to demonstrate the clinical utility of BMs derived from Magnetospirillum gryphiswaldense for use in anti-tumor immunotherapy. Bis(sulfosuccinimidyl) suberate (BS3) was used to prepare BM-anti-4-1BB antibody complexes. We used syngeneic TC-1 mouse models of cancer to investigate whether BMs combined with an anti-4-1BB agonistic antibodies could enhance the therapeutic effects of anti-4-1BB antibodies in localized disease settings. Anti-4-1BB antibodies were combined with purified BMs at a concentration of 168 mg antibody per milligram BM (mg IgG/mg BM) using BS3.The anti-4-1BB antibody-coupled BMs (BM-Ab complexes) and control BMs displayed similar morphologies and measurements when examined by transmission electron microscope (TEM). In a mouse tumor model, intravenous injection of BM-Abs combined with magnetic treatment resulted in greater tumor protection than did other treatment methods (P < 0.05). These results demonstrate the in vivo anti-tumor properties of BM-Abs complexes. The coupling of anti-4-1BB antibodies to magnetosomes may have potential for clinical application to antitumor antibody therapy. C 2019 small in size (40-120 nm) and are covered with a stable lipid membrane, which allows the magnetosomes to disperse very well [1]. The bilayer membrane component of BMs contains many amino groups, which can be combined with biological molecules that include enzymes, antibodies, and antitumor medicines [2,3]. Many in vitro results have demonstrated that BMs have many advantages over artificial iron oxide nanoparticles, particularly when the nanoparticles are used for biological applications [4][5][6].The cellular receptor 4-1BB (CD137) is a significant mediator of T-cell activation and persistence and exerts particularly strong effects on cytotoxic CD8+ T cells [7,8]. The administration of an anti-4-1BB antibody has been shown to eradicate small tumors when used alone or in combination with other antibodies in some mouse models [9,10].

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Type I IFN and not TNF, is Essential for Cyclic Di-nucleotide-elicited CTL by a Cytosolic Cross-presentation Pathway

Cited by 21 publications

References 54 publications

The STING ligand cGAMP potentiates the efficacy of vaccine-induced CD8+ T cells

The STING ligand cGAMP potentiates the efficacy of vaccine-induced CD8+ T cells

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

Preparation and anti‐tumor efficiency evaluation of bacterial magnetosome–anti‐4‐1BB antibody complex: Bacterial magnetosome as antibody carriers isolated from Magnetospirillum gryphiswaldense

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