Potent STING activation stimulates immunogenic cell death to enhance antitumor immunity in neuroblastoma
Background Neuroblastoma (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 pati...
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BMJ Publishing Group
2020-05-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/1/e000282.full |
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| author | Marjan Rafat Justin M. Balko Lihong Wang-Bishop Mohamed Wehbe Daniel Shae Jamaal James Benjamin C. Hacker Kyle Garland Plamen P. Chistov John T. Wilson |
| author_facet | Marjan Rafat Justin M. Balko Lihong Wang-Bishop Mohamed Wehbe Daniel Shae Jamaal James Benjamin C. Hacker Kyle Garland Plamen P. Chistov John T. Wilson |
| author_sort | Marjan Rafat |
| collection | DOAJ |
| description | Background Neuroblastoma (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.Methods To 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.Results The 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.Conclusions We 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. |
| format | Article |
| id | doaj-art-a8a0c7ce157e44508b8c85eea821760e |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-05-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-a8a0c7ce157e44508b8c85eea821760e2024-11-08T16:50:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-05-018110.1136/jitc-2019-000282Potent STING activation stimulates immunogenic cell death to enhance antitumor immunity in neuroblastomaMarjan Rafat0Justin M. Balko1Lihong Wang-Bishop2Mohamed Wehbe3Daniel Shae4Jamaal James5Benjamin C. Hacker6Kyle Garland7Plamen P. Chistov8John T. Wilson9Aff496 grid.168010.e0000000419368956Stanford Department of Radiation OncologyStanford University School of Medicine Stanford CA USA2 Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA1 Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee, USA1 Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee, USA1 Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee, USA2 Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA1 Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee, USA1 Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee, USA1 Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee, USA1 Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee, USABackground Neuroblastoma (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.Methods To 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.Results The 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.Conclusions We 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.https://jitc.bmj.com/content/8/1/e000282.full |
| spellingShingle | Marjan Rafat Justin M. Balko Lihong Wang-Bishop Mohamed Wehbe Daniel Shae Jamaal James Benjamin C. Hacker Kyle Garland Plamen P. Chistov John T. Wilson Potent STING activation stimulates immunogenic cell death to enhance antitumor immunity in neuroblastoma Journal for ImmunoTherapy of Cancer |
| title | Potent STING activation stimulates immunogenic cell death to enhance antitumor immunity in neuroblastoma |
| title_full | Potent STING activation stimulates immunogenic cell death to enhance antitumor immunity in neuroblastoma |
| title_fullStr | Potent STING activation stimulates immunogenic cell death to enhance antitumor immunity in neuroblastoma |
| title_full_unstemmed | Potent STING activation stimulates immunogenic cell death to enhance antitumor immunity in neuroblastoma |
| title_short | Potent STING activation stimulates immunogenic cell death to enhance antitumor immunity in neuroblastoma |
| title_sort | potent sting activation stimulates immunogenic cell death to enhance antitumor immunity in neuroblastoma |
| url | https://jitc.bmj.com/content/8/1/e000282.full |
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