Growing tumors induce a local STING dependent Type I IFN response in dendritic cells

Andzinski, Lisa; Spanier, Julia; Kasnitz, Nadine; Kröger, Andrea; Jin, Lei; Brinkmann, Melanie M.; Kalinke, Ulrich; Weiß, Siegfried; Jabłońska, Jadwiga

doi:10.1002/ijc.30159

Cited by 49 publications

(30 citation statements)

References 51 publications

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“…It was found STING-deficient mice are prone to developing several types of cancer and have poor survival under a tumor burden, whereas stimulation of STING can elicit robust immunity to tumors (225)(226)(227). A mechanism is many cancer cells expressing cGAS can recognize cytosolic DNA and produce cGAMP to stimulate secretion of type-I IFN through STING (228,229). Excessive expression of TREX1 in cancer cells, which can be induced by radiotherapy, attenuates this progression (228).…”

Section: Cgas-sting Pathway In Cancermentioning

confidence: 99%

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Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

2020

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Double-stranded DNA (dsDNA) sensor cyclic-GMP-AMP synthase (cGAS) along with the downstream stimulator of interferon genes (STING) acting as essential immunesurveillance mediators have become hot topics of research. The intrinsic function of the cGAS-STING pathway facilitates type-I interferon (IFN) inflammatory signaling responses and other cellular processes such as autophagy, cell survival, senescence. cGAS-STING pathway interplays with other innate immune pathways, by which it participates in regulating infection, inflammatory disease, and cancer. The therapeutic approaches targeting this pathway show promise for future translation into clinical applications. Here, we present a review of the important previous works and recent advances regarding the cGAS-STING pathway, and provide a comprehensive understanding of the modulatory pattern of the cGAS-STING pathway under multifarious pathologic states.

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Section: Cgas-sting Pathway In Cancermentioning

confidence: 99%

“…Dendritic Cells are the main source of type-I IFN in several types of TMEs and are dependent on STING signaling (229). More preferentially than macrophages, infiltrating DCs take up tumor-derived DNA or cGAMP from dying cell fragments by phagocytosis (27,29,129,226,233).…”

Section: Cgas-sting Pathway In Cancermentioning

confidence: 99%

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

2020

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“…Antigen presenting DC internalize tumor-derived DNA via phagocytosis of tumor cell debris [42 •• ,43 •• ], creating an IFN-I-driven autocrine loop that drives CD8+ T cell priming and activation [42 •• ,43 •• ,44 •• ,53]. Although extrinsic sensing of tumor cell debris is confined to cells with phagocytic capability, it appears that ubiquitous cell-intrinsic mechanisms exist for sensing genotoxic stress and DNA damage, which has long been appreciated as a robust inducer of the IFN-I response [54,55].…”

Section: Cancer Cancer Therapy and Genotoxic Stressmentioning

confidence: 99%

Cytosolic sensing of immuno-stimulatory DNA, the enemy within

Dhanwani

Takahashi

Sharma

2018

Current Opinion in Immunology

100

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In the cytoplasm, DNA is sensed as a universal danger signal by the innate immune system. Cyclic GMP–AMP synthase (cGAS) is a cytosolic DNA sensor/enzyme that catalyzes formation of 2′–5′-cGAMP, an atypical cyclic di-nucleotide second messenger that binds and activates the Stimulator of Interferon Genes (STING), resulting in recruitment of Tank Binding Kinase 1 (TBK1), activation of the transcription factor Interferon Regulatory Factor 3 (IRF3), and trans-activation of innate immune response genes, including type I Interferon cytokines (IFN-I). Activation of the pro-inflammatory cGAS–STING–IRF3 response is triggered by direct recognition of the DNA genomes of bacteria and viruses, but also during RNA virus infection, neoplastic transformation, tumor immunotherapy and systemic auto-inflammatory diseases. In these circumstances, the source of immuno-stimulatory DNA has often represented a fundamental yet poorly understood aspect of the response. This review focuses on recent findings related to cGAS activation by an array of self-derived DNA substrates, including endogenous retroviral elements, mitochondrial DNA (mtDNA) and micronuclei generated as a result of genotoxic stress and DNA damage. These findings emphasize the role of the cGAS axis as a cell-intrinsic innate immune response to a wide variety of genomic insults.

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“…Although there has been considerable evidence that dendritic cells play a vital role in the anti-tumoral immune response (Andzinski et al, 2016;Carozza et al, 2020;Laursen et al, 2018), there were no differences in STING pathway activation in the presence or absence of tumor-derived extracellular cGAMP (Figure S5F), suggesting that their role in anti-tumoral immunity is downstream of a direct cGAMP responder cell. Likewise, there were no differences observed in B cells (Figure S5G).…”

Section: Intratumoral Macrophages and Nk Cells Directly Respond To Tumentioning

confidence: 96%

“…While it is known that this transfer of cGAMP ultimately results in downstream immune activation, it is unknown which cell types directly respond to tumor-derived extracellular cGAMP. Several studies have suggested that CD11c + dendritic cells are the cGAMP-sensing cells in tumors (Andzinski et al, 2016;Carozza et al, 2020;Laursen et al, 2018), while others have identified macrophages (Zhou et al, 2020b), NK cells (Marcus et al, 2018;Nicolai et al, 2020), endothelial cells (Demaria et al, 2015), and CD11b + myeloid cells (Marcus et al, 2018). However, these studies either relied on exogenous cGAMP administration or did not directly measure activation of the STING pathway in different cell types.…”

Section: Introductionmentioning

confidence: 99%

Human SLC46A2 is the dominant cGAMP importer in extracellular cGAMP-sensing macrophages and monocytes

Cordova

Ritchie

Böhnert

et al. 2020

Preprint

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Administration of exogenous CDNs to activate the cGAMP-STING pathway is a promising therapeutic strategy to unleash the full potential of cancer immunotherapy. This strategy mirrors the role of endogenous extracellular cGAMP, which we recently described as an immunotransmitter exported by cancer cells and imported into local responder cells of unknown identities to promote anti-tumoral immunity, with irradiation enhancing this effect. Here, in low-dose irradiated murine tumors, we identified CD4 + T cells, M1 macrophages, and NKG2D Low NK cells as cGAMP responder cells that have decreased STING activation upon depletion of extracellular cGAMP. At higher doses of radiation, extracellular cGAMP promoted the death of T cells and macrophages. Furthermore, we identified the orphan protein SLC46A2 as the dominant importer of cGAMP and select bacterial CDNs in human macrophages and monocytes. Together, we provide the first cellular and molecular mechanisms of cGAMP as an immunotransmitter, paving the way for effective STING pathway therapeutics.

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Growing tumors induce a local STING dependent Type I IFN response in dendritic cells

Cited by 49 publications

References 51 publications

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

Cytosolic sensing of immuno-stimulatory DNA, the enemy within

Human SLC46A2 is the dominant cGAMP importer in extracellular cGAMP-sensing macrophages and monocytes

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