STING Pathway Activation Stimulates Potent Immunity against Acute Myeloid Leukemia

Curran, Emily; Chen, Xiufen; Corrales, Leticia; Kline, Douglas E.; Dubensky, Thomas W.; Duttagupta, Priyanka; Kortylewski, Marcin; Kline, Justin

doi:10.1016/j.celrep.2016.05.023

Cited by 139 publications

(114 citation statements)

References 30 publications

(51 reference statements)

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“…26,27,36 Consistent with previous reports that STING plays a central role in DNA recognition to drive proinflammatory cytokine and type I IFN generation, our studies led to similar findings in which absence of STING diminished AP-associated inflammation, whereas its activation led to worsening of disease. Although in development, currently pharmacologic inhibitors of STING are nonexistent, and such studies will be important in targeting proinflammatory responses in AP.…”

Section: Discussionsupporting

confidence: 91%

STING Signaling Promotes Inflammation in Experimental Acute Pancreatitis

et al. 2018

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BACKGROUND & AIMS: Acute pancreatitis (AP) is characterized by severe inflammation and acinar cell death. Transmembrane protein 173 (TMEM173 or STING) is a DNA sensor adaptor protein on immune cells that recognizes cytosolic nucleic acids and transmits signals that activate production of interferons and the innate immune response. We investigated whether leukocyte STING signaling mediates inflammation in mice with AP. METHODS: We induced AP in C57BL/6J mice (control) and C57BL/6J-Tmem173gt/J mice (STING-knockout mice) by injection of cerulein or placement on choline-deficient DL-ethionine supplemented diet. In some mice, STING signaling was induced by administration of a pharmacologic agonist. AP was also induced in C57BL/6J mice with bone marrow transplants from control or STING-knockout mice and in mice with disruption of the cyclic GMP-AMP synthase (Cgas) gene. Pancreata were collected, analyzed by histology, and acini were isolated and analyzed by flow cytometry, quantitative polymerase chain reaction, immunoblots, and enzyme-linked immunosorbent assay. Bone-marrow–derived macrophages were collected from mice and tested for their ability to detect DNA from dying acinar cells in the presence and absence of deoxyribonuclease (DNaseI). RESULTS: STING signaling was activated in pancreata from mice with AP but not mice without AP. STING-knockout mice developed less severe AP (less edema, inflammation, and markers of pancreatic injury) than control mice, whereas mice given a STING agonist developed more severe AP than controls. In immune cells collected from pancreata, STING was expressed predominantly in macrophages. Levels of cGAS were increased in mice with vs without AP, and cGAS-knockout mice had decreased edema, inflammation, and other markers of pancreatic injury upon induction of AP than control mice. Wild-type mice given bone marrow transplants from STING-knockout mice had less pancreatic injury and lower serum levels of lipase and pancreatic trypsin activity following induction of AP than mice given wildtype bone marrow. DNA from dying acinar cells activated STING signaling in macrophages, which was inhibited by addition of DNaseI. CONCLUSIONS: In mice with AP, STING senses acinar cell death (by detecting DNA from dying acinar cells) and activates a signaling pathway that promotes inflammation. Macrophages express STING and activate pancreatic inflammation in AP.

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Section: Discussionsupporting

confidence: 91%

STING Signaling Promotes Inflammation in Experimental Acute Pancreatitis

et al. 2018

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“…[101, 112] Given that STING signaling activates type I IFN signaling, tumors that lack baseline type I IFN signaling may be ideal targets for treatment with a STING agonist, and STING agonists have been shown to promote IFN signaling and extend survival in two AML mouse models. [113]…”

Section: Dna Repair Factors Beyond Mutational Load Can Also Impact Anmentioning

confidence: 99%

DNA Damage and Repair Biomarkers of Immunotherapy Response

et al. 2017

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DNA damaging agents are widely used in clinical oncology and exploit deficiencies in tumor DNA repair. Given the expanding role of immune checkpoint blockade as a therapeutic strategy, the interaction of tumor DNA damage with the immune system has recently come into focus, and it is now clear that the tumor DNA repair landscape has an important role in driving response to immune checkpoint blockade. Here, we summarize the mechanisms by which DNA damage and genomic instability have been found to shape the anti-tumor immune response and describe clinical efforts to use DNA repair biomarkers to guide use of immune-directed therapies.

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“…As previously demonstrated, 15 host type I IFN signaling played no role in regulating survival of mice with control AML. Strikingly, however, the survival benefit associated with CRT expression on AML cells was almost completely abolished in Ifnar − / − hosts.…”

Section: Discussionmentioning

confidence: 69%

“…However, the observation that CRT stimulates type I IFN suggests that activating this pathway, for example, with stimulator of interferon genes (STING) agonists, 15,24 may be an efficacious alternative immunotherapeutic strategy. Regardless, the identification of type I IFN as a mechanism through which CRT translocation stimulates host antitumor immunity represents an important step forward in our understanding of how cancers are sensed by the host immune system.…”

Section: Discussionmentioning

confidence: 99%

“…In a recent study, the degree of cell-surface CRT expression on human acute myeloid leukemia (AML) cells was found to correlate with enhanced T-cell immunity to AML-associated antigens and improved clinical outcomes 14 . In addition, our laboratory is interested in characterizing pathways that promote innate immune sensing of AML 15 . With these notions in mind, we sought to investigate mechanisms through which CRT translocation on AML cells might promote anti-leukemia immunity.…”

Section: Introductionmentioning

confidence: 99%

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Calreticulin promotes immunity and type I interferon-dependent survival in mice with acute myeloid leukemia

et al. 2017

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Exposure of cancer cells to particular chemotherapeutic agents or γ-irradiation induces a form of cell death that stimulates an immune response in mice. This “immunogenic cell death” requires calreticulin (CRT) translocation to the plasma membrane, which has been shown to promote cancer cell phagocytosis. However, it remains unclear whether the effect of CRT on cancer cell phagocytosis is alone sufficient to affect tumor immunity. Acute myeloid leukemia (AML) cells expressing cell-surface CRT were generated in order to characterize the mechanism(s) through which CRT activates tumor immune responses. Potent immune-mediated control or rejection of AML was observed in mice with CRT-expressing leukemia. The “CRT effect” was ultimately T-cell dependent, but dendritic cells (DCs), and CD8α+ DCs in particular, were also necessary, indicating that CRT might act directly on these DCs. CRT-expressing AML cells were slightly more susceptible to phagocytosis by DCs in vivo, but this effect was unlikely to explain the potent immunity observed. CRT did not affect classical DC maturation markers, but induced expression of type I interferon (IFN), which was critical for its positive effect on survival. In conclusion, CRT functions as a “danger signal” that promotes a host type I IFN response associated with the induction of potent leukemia-specific T-cell immunity.

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STING Pathway Activation Stimulates Potent Immunity against Acute Myeloid Leukemia

Cited by 139 publications

References 30 publications

STING Signaling Promotes Inflammation in Experimental Acute Pancreatitis

STING Signaling Promotes Inflammation in Experimental Acute Pancreatitis

DNA Damage and Repair Biomarkers of Immunotherapy Response

Calreticulin promotes immunity and type I interferon-dependent survival in mice with acute myeloid leukemia

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