A nanoparticle-incorporated STING activator enhances antitumor immunity in PD-L1–insensitive models of triple-negative breast cancer

Cheng, Ning; Watkins-Schulz, Rebekah; Junkins, Robert D.; David, Clément N.; Johnson, Brandon M.; Montgomery, Stephanie A.; Peine, Kevin J.; Darr, David B.; Yuan, Hong; McKinnon, Karen P.; Liu, Qi; Miao, Lei; Huang, Leaf; Bachelder, Eric M.; Ainslie, Kristy M.; Ting, Jenny P.-Y.

doi:10.1172/jci.insight.120638

Cited by 184 publications

(159 citation statements)

References 64 publications

(68 reference statements)

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“…Packaging cGAMP in liposomal nanoparticles has demonstrated improved cellular uptake and better tumor control in transplantable and genetically engineered triple negative breast cancer models as well as the B16.F10 melanoma model . Another study found that liposomal formulated STING agonist can cause loss of APC viability, so the authors chose to load a STING agonist ex vivo into exosomes instead (Exosting).…”

Section: Sting Pathway Involvement In Anti‐tumor Immunity In Preclinimentioning

confidence: 99%

“…121 Packaging cGAMP in liposomal nanoparticles has demonstrated improved cellular uptake and better tumor control in transplantable and genetically engineered triple negative breast cancer models as well as the B16.F10 melanoma model. 122 Another study found that liposomal formulated STING agonist can cause loss of APC viability, so the authors chose to load a STING agonist ex vivo into exosomes instead (Exosting). ExoSTING induced superior IFN-β production compared to soluble STING agonists and the responding mice were protected against tumor re-challenge (Society for ImmunoTherapy of Cancer Annual Meeting 2018 Poster P618).…”

Section: Novel Strategies For Sting Agonist Delivery By the Systemimentioning

confidence: 99%

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STING pathway agonism as a cancer therapeutic

Flood

Higgs

et al. 2019

Immunological Reviews

211

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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Section: Sting Pathway Involvement In Anti‐tumor Immunity In Preclinimentioning

confidence: 99%

Section: Novel Strategies For Sting Agonist Delivery By the Systemimentioning

confidence: 99%

STING pathway agonism as a cancer therapeutic

Flood

Higgs

et al. 2019

Immunological Reviews

211

183

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“…While promising immunotherapeutic agents, CDNs-anionic, highly water-soluble molecules-suffer from low bioavailability and poor drug-like properties. [26][27][28][29][30][31] As a result, CDNs do not readily cross the cellular plasma membrane leading to limited access to the cytosol where STING is located. 29 30 To address these drug delivery barriers, we have recently described STINGactivating nanoparticles (STING-NPs)-endosomedestabilizing polymer vesicles (polymersomes) optimized for intracellular delivery of 2'3'-cGAMP (cyclic guanosine monophosphate-adenosine monophosphate, cyclic(G(2',5')pA(3',5')p)), the natural and endogenous high affinity ligand of STING.…”

Section: Introductionmentioning

confidence: 99%

Potent STING activation stimulates immunogenic cell death to enhance antitumor immunity in neuroblastoma

Wang-Bishop

Wehbe

Shae

et al. 2020

J Immunother Cancer

108

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BackgroundNeuroblastoma (NB) is a childhood cancer for which new treatment options are needed. The success of immune checkpoint blockade in the treatment of adult solid tumors has prompted the exploration of immunotherapy in NB; however, clinical evidence indicates that the vast majority of NB patients do not respond to single-agent checkpoint inhibitors. This motivates a need for therapeutic strategies to increase NB tumor immunogenicity. The goal of this study was to evaluate a new immunotherapeutic strategy for NB based on potent activation of the stimulator of interferon genes (STING) pathway.MethodsTo promote STING activation in NB cells and tumors, we utilized STING-activating nanoparticles (STING-NPs) that are designed to mediate efficient cytosolic delivery of the endogenous STING ligand, 2’3’-cGAMP. We investigated tumor-intrinsic responses to STING activation in both MYCN-amplified and non-amplified NB cell lines, evaluating effects on STING signaling, apoptosis, and the induction of immunogenic cell death. The effects of intratumoral administration of STING-NPs on CD8+T cell infiltration, tumor growth, and response to response to PD-L1 checkpoint blockade were evaluated in syngeneic models of MYCN-amplified and non-amplified NB.ResultsThe efficient cytosolic delivery of 2’3’-cGAMP enabled by STING-NPs triggered tumor-intrinsic STING signaling effects in both MYCN-amplified and non-amplified NB cell lines, resulting in increased expression of interferon-stimulated genes and pro-inflammatory cytokines as well as NB cell death at concentrations 2000-fold to 10000-fold lower than free 2’3’-cGAMP. STING-mediated cell death in NB was associated with release or expression of several danger associated molecular patterns that are hallmarks of immunogenic cell death, which was further validated via cell-based vaccination and tumor challenge studies. Intratumoral administration of STING-NPs enhanced STING activation relative to free 2’3’-cGAMP in NB tumor models, converting poorly immunogenic tumors into tumoricidal and T cell-inflamed microenvironments and resulting in inhibition of tumor growth, increased survival, and induction of immunological memory that protected against tumor re-challenge. In a model of MYCN-amplified NB, STING-NPs generated an abscopal response that inhibited distal tumor growth and improved response to PD-L1 immune checkpoint blockade.ConclusionsWe have demonstrated that activation of the STING pathway, here enabled by a nanomedicine approach, stimulates immunogenic cell death and remodels the tumor immune microenvironment to inhibit NB tumor growth and improve responses to immune checkpoint blockade, providing a multifaceted immunotherapeutic approach with potential to enhance immunotherapy outcomes in NB.

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“…Having identified T cells as direct cGAMP responders, we next turned our analysis to other immune cell types within the tumor. Numerous studies have identified macrophages as a key cell type in the STING-mediated antitumoral immune response (Cheng et al, 2018;Ohkuri et al, 2017;Zhou et al, 2020b). Here, we provide evidence that F4/80 + macrophages directly respond to tumor-derived extracellular cGAMP.…”

Section: Intratumoral Macrophages and Nk Cells Directly Respond To Tumentioning

confidence: 54%

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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A nanoparticle-incorporated STING activator enhances antitumor immunity in PD-L1–insensitive models of triple-negative breast cancer

Cited by 184 publications

References 64 publications

STING pathway agonism as a cancer therapeutic

STING pathway agonism as a cancer therapeutic

Potent STING activation stimulates immunogenic cell death to enhance antitumor immunity in neuroblastoma

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

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