Intrinsic antiproliferative activity of the innate sensor STING in T lymphocytes

Cerboni, Silvia; Jeremiah, Nadia; Gentili, Matteo; Gehrmann, Ulf; Conrad, Cécile; Stolzenberg, Marie-Claude; Pïcard, Capucine; Neven, Bénédicte; Fischer, Alain; Amigorena, Sébastian; Rieux-Laucat, Frédéric; Manel, Nicolas

doi:10.1084/jem.20161674

Cited by 230 publications

(264 citation statements)

References 42 publications

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“…Interestingly, the most frequent virus isolated was rhinovirus, which may be a direct consequence of effective type I IFN inhibition by ruxolitinib at least in respiratory epithelial cells, where IFN-β is required to control rhinovirus [16,17]. On the other end, these infections might result from a cumulative effect of the drug with the reported developmental and in vitro proliferative defects of STING mutant T lymphocytes [18,19]. Considering the severity of lung disease and the lymphopenia ( Table 2) present before ruxolitinib treatment, P2 was started on antibiotic prophylaxis with Bactrim and Azithromycin; that, however, did not seem to prevent the febrile episodes, mostly if not always caused by viral pathogens.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Adverse Events During Janus Kinase Inhibitor Treatment of SAVI Syndrome

et al. 2019

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Objectives Mutations affecting the TMEM173 gene cause STING-associated vasculopathy with onset in infancy (SAVI). No standard immunosuppressive treatment approach is able to control disease progression in patients with SAVI. We studied the efficacy and safety of targeting type I IFN signaling with the Janus kinase inhibitor, ruxolitinib. Methods We used DNA sequencing to identify mutations in TMEM173 in patients with peripheral blood type I IFN signature. The JAK1/2 inhibitor ruxolitinib was administered on an off-label basis. Results We identified three patients with SAVI presenting with skin involvement and progressive severe interstitial lung disease. Indirect echocardiographic signs of pulmonary hypertension were present in one case. Following treatment with ruxolitinib, we observed improvements of respiratory function including increased forced vital capacity in two patients, with discontinuation of oxygen therapy and resolution of echocardiographic abnormalities in one case. Efficacy was persistent in one patient and only transitory in the other two patients. Clinical control of skin complications was obtained, and one patient discontinued steroid Stefano Volpi and Antonella Insalaco contributed equally.Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10875-019-00645-0) contains supplementary material, which is available to authorized users. treatment. One patient, who presented with kidney involvement, showed resolution of hematuria. One patient experienced increased recurrence of severe viral respiratory infections. Monitoring of peripheral blood type I interferon signature during ruxolitinib treatment did not show a stable decrease. Conclusions We conclude that targeting type I IFN receptor signaling may represent a promising therapeutic option for a subset of patients with SAVI syndrome and severe lung involvement. However, the occurrence of viral respiratory infection might represent an important cautionary note for the application of such form of treatment.

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Section: Discussionmentioning

confidence: 99%

Efficacy and Adverse Events During Janus Kinase Inhibitor Treatment of SAVI Syndrome

et al. 2019

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“…Persistent STING signaling reportedly affects T cell function as well. T cells isolated from patients with constitutively activating STING genetic mutations had fewer circulating memory T cells . Based on this biology, STING agonists have also been evaluated as a potential therapeutic agent for T cell malignancies.…”

Section: Basic Biology Of the Sting Pathwaymentioning

confidence: 99%

“…T cells isolated from patients with constitutively activating STING genetic mutations had fewer circulating memory T cells. 94 Based on this biology, STING agonists have also been evaluated as a potential therapeutic agent for T cell malignancies. Interestingly, STING agonists delayed tumor growth of T-ALL murine tumors even in STING-deficient hosts, suggesting tumor-intrinsic STING activation could have beneficial anti-tumor effects in T-lineage malignancies.…”

Section: Cell Type-specific Effects Of Sting Signalingmentioning

confidence: 99%

STING pathway agonism as a cancer therapeutic

Flood

Higgs

et al. 2019

Immunological Reviews

243

183

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The fact that a subset of human cancers showed evidence for a spontaneous adaptive immune response as reflected by the T cell‐inflamed tumor microenvironment phenotype led to the search for candidate innate immune pathways that might be driving such endogenous responses. Preclinical studies indicated a major role for the host STING pathway, a cytosolic DNA sensing pathway, as a proximal event required for optimal type I interferon production, dendritic cell activation, and priming of CD8+ T cells against tumor‐associated antigens. STING agonists are therefore being developed as a novel cancer therapeutic, and a greater understanding of STING pathway regulation is leading to a broadened list of candidate immune regulatory targets. Early phase clinical trials of intratumoral STING agonists are already showing promise, alone and in combination with checkpoint blockade. Further advancement will derive from a deeper understanding of STING pathway biology as well as mechanisms of response vs resistance in individual cancer patients.

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“…While extracellular cGAMP signaling in M1 macrophages and NK cells resulted in increased IFN-I production, extracellular cGAMP signaling was toxic to T cells when combined with ionizing radiation. There is a substantial body of evidence linking STING activation to immune cell death or antiproliferation (Cerboni et al, 2017;Gaidt et al, 2017;Gulen et al, 2017;Larkin et al, 2017;Tang et al, 2016); indeed, 2'3'-CDA S , one of the cGAMP analogs in clinical trials, has a narrow therapeutic window due to T cell ablation at higher doses (Sivick et al, 2018). Consequently, the impact of STING signaling on T cell viability should be considered when combining radiation, STING agonists, and/or CTLA-4/PD-1 checkpoint inhibitor therapies, which are dependent on T cells for their efficacy (Blank et al, 2004;Iwai et al, 2002;Leach et al, 1996;Shrikant et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…While cGAMP leads to a strong IFN-I response in some cell types, there is mounting evidence that the effects of cGAMP signaling are cell-type specific. For example, it has been shown that T cells die in response to cGAMP signaling (Cerboni et al, 2017;Gulen et al, 2017;Larkin et al, 2017). Additionally, a recent study showed that cGAMP signaling in different cell types in the mouse lung led to different levels of IFN-I production, with some cell types unable to produce enough IFN-I for effective immunity (Wang et al, 2020).…”

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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Intrinsic antiproliferative activity of the innate sensor STING in T lymphocytes

Abstract: The innate sensor STING is critical for innate immune activation, but its role in adaptive immunity is unknown. By studying pathogenic mutations in STING found in patients, Cerboni et al. show that active STING inhibits proliferation in T lymphocytes.

Cited by 230 publications

References 42 publications

Efficacy and Adverse Events During Janus Kinase Inhibitor Treatment of SAVI Syndrome

Efficacy and Adverse Events During Janus Kinase Inhibitor Treatment of SAVI Syndrome

STING pathway agonism as a cancer therapeutic

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

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