STING agonism orchestrates myeloid-predominant tumor necrosis preceding T cell-dependent regression in osteosarcoma

Elizabeth P. Young; Christine A. Johnson; Alex G. Lee; Douglass Morris II; Georgia M. Edmondson; Alfonso G. Ramirez-Ristori; Jessica Tsui; Marcus R. Breese; Juan Antonio Camara Serrano; Courtney R. Schott; Clare L. Abram; Stanley G. Leung; Leanne C. Sayles; Aafrin M. Pettiwala; Vanessa S. Gutierrez Vera; Clifford A. Lowell; Alexis J. Combes; Troy A. McEachron; E. Alejandro Sweet-Cordero

doi:10.1172/jci.insight.201731

¹Division of Pediatric Oncology, UCSF, San Francisco, United States of America

²Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

³UCSF CoLabs, UCSF, San Francisco, United States of America

⁴Center for Computational Biology and Bioinformatics, Department of Medical, Indiana University School of Medicine, Indianapolis, United States of America

⁵Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, United States of America

⁶Department of Pathobiology, University of Guelph, Ontario Veterinary College, Guelph, Canada

⁷Department of Laboratory Medicine, UCSF, San Francisco, United States of America

⁸Division of Radiation Oncology, UCSF, San Francisco, United States of America

⁹Helen Diller Family Comprehensive Cancer, UCSF, San Francisco, United States of America

¹⁰Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Besthesda, United States of America

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¹Division of Pediatric Oncology, UCSF, San Francisco, United States of America

²Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

³UCSF CoLabs, UCSF, San Francisco, United States of America

⁴Center for Computational Biology and Bioinformatics, Department of Medical, Indiana University School of Medicine, Indianapolis, United States of America

⁵Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, United States of America

⁶Department of Pathobiology, University of Guelph, Ontario Veterinary College, Guelph, Canada

⁷Department of Laboratory Medicine, UCSF, San Francisco, United States of America

⁸Division of Radiation Oncology, UCSF, San Francisco, United States of America

⁹Helen Diller Family Comprehensive Cancer, UCSF, San Francisco, United States of America

¹⁰Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Besthesda, United States of America

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¹Division of Pediatric Oncology, UCSF, San Francisco, United States of America

²Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

³UCSF CoLabs, UCSF, San Francisco, United States of America

⁴Center for Computational Biology and Bioinformatics, Department of Medical, Indiana University School of Medicine, Indianapolis, United States of America

⁵Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, United States of America

⁶Department of Pathobiology, University of Guelph, Ontario Veterinary College, Guelph, Canada

⁷Department of Laboratory Medicine, UCSF, San Francisco, United States of America

⁸Division of Radiation Oncology, UCSF, San Francisco, United States of America

⁹Helen Diller Family Comprehensive Cancer, UCSF, San Francisco, United States of America

¹⁰Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Besthesda, United States of America

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¹Division of Pediatric Oncology, UCSF, San Francisco, United States of America

²Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

³UCSF CoLabs, UCSF, San Francisco, United States of America

⁴Center for Computational Biology and Bioinformatics, Department of Medical, Indiana University School of Medicine, Indianapolis, United States of America

⁵Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, United States of America

⁶Department of Pathobiology, University of Guelph, Ontario Veterinary College, Guelph, Canada

⁷Department of Laboratory Medicine, UCSF, San Francisco, United States of America

⁸Division of Radiation Oncology, UCSF, San Francisco, United States of America

⁹Helen Diller Family Comprehensive Cancer, UCSF, San Francisco, United States of America

¹⁰Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Besthesda, United States of America

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¹Division of Pediatric Oncology, UCSF, San Francisco, United States of America

²Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

³UCSF CoLabs, UCSF, San Francisco, United States of America

⁴Center for Computational Biology and Bioinformatics, Department of Medical, Indiana University School of Medicine, Indianapolis, United States of America

⁵Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, United States of America

⁶Department of Pathobiology, University of Guelph, Ontario Veterinary College, Guelph, Canada

⁷Department of Laboratory Medicine, UCSF, San Francisco, United States of America

⁸Division of Radiation Oncology, UCSF, San Francisco, United States of America

⁹Helen Diller Family Comprehensive Cancer, UCSF, San Francisco, United States of America

¹⁰Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Besthesda, United States of America

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¹Division of Pediatric Oncology, UCSF, San Francisco, United States of America

²Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

³UCSF CoLabs, UCSF, San Francisco, United States of America

⁴Center for Computational Biology and Bioinformatics, Department of Medical, Indiana University School of Medicine, Indianapolis, United States of America

⁵Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, United States of America

⁶Department of Pathobiology, University of Guelph, Ontario Veterinary College, Guelph, Canada

⁷Department of Laboratory Medicine, UCSF, San Francisco, United States of America

⁸Division of Radiation Oncology, UCSF, San Francisco, United States of America

⁹Helen Diller Family Comprehensive Cancer, UCSF, San Francisco, United States of America

¹⁰Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Besthesda, United States of America

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¹Division of Pediatric Oncology, UCSF, San Francisco, United States of America

²Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

³UCSF CoLabs, UCSF, San Francisco, United States of America

⁴Center for Computational Biology and Bioinformatics, Department of Medical, Indiana University School of Medicine, Indianapolis, United States of America

⁵Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, United States of America

⁶Department of Pathobiology, University of Guelph, Ontario Veterinary College, Guelph, Canada

⁷Department of Laboratory Medicine, UCSF, San Francisco, United States of America

⁸Division of Radiation Oncology, UCSF, San Francisco, United States of America

⁹Helen Diller Family Comprehensive Cancer, UCSF, San Francisco, United States of America

¹⁰Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Besthesda, United States of America

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¹Division of Pediatric Oncology, UCSF, San Francisco, United States of America

²Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

³UCSF CoLabs, UCSF, San Francisco, United States of America

⁴Center for Computational Biology and Bioinformatics, Department of Medical, Indiana University School of Medicine, Indianapolis, United States of America

⁵Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, United States of America

⁶Department of Pathobiology, University of Guelph, Ontario Veterinary College, Guelph, Canada

⁷Department of Laboratory Medicine, UCSF, San Francisco, United States of America

⁸Division of Radiation Oncology, UCSF, San Francisco, United States of America

⁹Helen Diller Family Comprehensive Cancer, UCSF, San Francisco, United States of America

¹⁰Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Besthesda, United States of America

Find articles by Breese, M. in: PubMed | Google Scholar

¹Division of Pediatric Oncology, UCSF, San Francisco, United States of America

²Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

³UCSF CoLabs, UCSF, San Francisco, United States of America

⁴Center for Computational Biology and Bioinformatics, Department of Medical, Indiana University School of Medicine, Indianapolis, United States of America

⁵Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, United States of America

⁶Department of Pathobiology, University of Guelph, Ontario Veterinary College, Guelph, Canada

⁷Department of Laboratory Medicine, UCSF, San Francisco, United States of America

⁸Division of Radiation Oncology, UCSF, San Francisco, United States of America

⁹Helen Diller Family Comprehensive Cancer, UCSF, San Francisco, United States of America

¹⁰Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Besthesda, United States of America

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¹Division of Pediatric Oncology, UCSF, San Francisco, United States of America

²Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

³UCSF CoLabs, UCSF, San Francisco, United States of America

⁴Center for Computational Biology and Bioinformatics, Department of Medical, Indiana University School of Medicine, Indianapolis, United States of America

⁵Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, United States of America

⁶Department of Pathobiology, University of Guelph, Ontario Veterinary College, Guelph, Canada

⁷Department of Laboratory Medicine, UCSF, San Francisco, United States of America

⁸Division of Radiation Oncology, UCSF, San Francisco, United States of America

⁹Helen Diller Family Comprehensive Cancer, UCSF, San Francisco, United States of America

¹⁰Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Besthesda, United States of America

Find articles by Schott, C. in: PubMed | Google Scholar

¹Division of Pediatric Oncology, UCSF, San Francisco, United States of America

²Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

³UCSF CoLabs, UCSF, San Francisco, United States of America

⁴Center for Computational Biology and Bioinformatics, Department of Medical, Indiana University School of Medicine, Indianapolis, United States of America

⁵Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, United States of America

⁶Department of Pathobiology, University of Guelph, Ontario Veterinary College, Guelph, Canada

⁷Department of Laboratory Medicine, UCSF, San Francisco, United States of America

⁸Division of Radiation Oncology, UCSF, San Francisco, United States of America

⁹Helen Diller Family Comprehensive Cancer, UCSF, San Francisco, United States of America

¹⁰Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Besthesda, United States of America

Find articles by Abram, C. in: PubMed | Google Scholar

¹Division of Pediatric Oncology, UCSF, San Francisco, United States of America

²Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

³UCSF CoLabs, UCSF, San Francisco, United States of America

⁴Center for Computational Biology and Bioinformatics, Department of Medical, Indiana University School of Medicine, Indianapolis, United States of America

⁵Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, United States of America

⁶Department of Pathobiology, University of Guelph, Ontario Veterinary College, Guelph, Canada

⁷Department of Laboratory Medicine, UCSF, San Francisco, United States of America

⁸Division of Radiation Oncology, UCSF, San Francisco, United States of America

⁹Helen Diller Family Comprehensive Cancer, UCSF, San Francisco, United States of America

¹⁰Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Besthesda, United States of America

Find articles by Leung, S. in: PubMed | Google Scholar |

¹Division of Pediatric Oncology, UCSF, San Francisco, United States of America

²Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

³UCSF CoLabs, UCSF, San Francisco, United States of America

⁴Center for Computational Biology and Bioinformatics, Department of Medical, Indiana University School of Medicine, Indianapolis, United States of America

⁵Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, United States of America

⁶Department of Pathobiology, University of Guelph, Ontario Veterinary College, Guelph, Canada

⁷Department of Laboratory Medicine, UCSF, San Francisco, United States of America

⁸Division of Radiation Oncology, UCSF, San Francisco, United States of America

⁹Helen Diller Family Comprehensive Cancer, UCSF, San Francisco, United States of America

¹⁰Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Besthesda, United States of America

Find articles by Sayles, L. in: PubMed | Google Scholar |

¹Division of Pediatric Oncology, UCSF, San Francisco, United States of America

²Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

³UCSF CoLabs, UCSF, San Francisco, United States of America

⁴Center for Computational Biology and Bioinformatics, Department of Medical, Indiana University School of Medicine, Indianapolis, United States of America

⁵Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, United States of America

⁶Department of Pathobiology, University of Guelph, Ontario Veterinary College, Guelph, Canada

⁷Department of Laboratory Medicine, UCSF, San Francisco, United States of America

⁸Division of Radiation Oncology, UCSF, San Francisco, United States of America

⁹Helen Diller Family Comprehensive Cancer, UCSF, San Francisco, United States of America

¹⁰Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Besthesda, United States of America

Find articles by Pettiwala, A. in: PubMed | Google Scholar

¹Division of Pediatric Oncology, UCSF, San Francisco, United States of America

²Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

³UCSF CoLabs, UCSF, San Francisco, United States of America

⁴Center for Computational Biology and Bioinformatics, Department of Medical, Indiana University School of Medicine, Indianapolis, United States of America

⁵Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, United States of America

⁶Department of Pathobiology, University of Guelph, Ontario Veterinary College, Guelph, Canada

⁷Department of Laboratory Medicine, UCSF, San Francisco, United States of America

⁸Division of Radiation Oncology, UCSF, San Francisco, United States of America

⁹Helen Diller Family Comprehensive Cancer, UCSF, San Francisco, United States of America

¹⁰Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Besthesda, United States of America

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¹Division of Pediatric Oncology, UCSF, San Francisco, United States of America

²Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

³UCSF CoLabs, UCSF, San Francisco, United States of America

⁴Center for Computational Biology and Bioinformatics, Department of Medical, Indiana University School of Medicine, Indianapolis, United States of America

⁵Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, United States of America

⁶Department of Pathobiology, University of Guelph, Ontario Veterinary College, Guelph, Canada

⁷Department of Laboratory Medicine, UCSF, San Francisco, United States of America

⁸Division of Radiation Oncology, UCSF, San Francisco, United States of America

⁹Helen Diller Family Comprehensive Cancer, UCSF, San Francisco, United States of America

¹⁰Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Besthesda, United States of America

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¹Division of Pediatric Oncology, UCSF, San Francisco, United States of America

²Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

³UCSF CoLabs, UCSF, San Francisco, United States of America

⁴Center for Computational Biology and Bioinformatics, Department of Medical, Indiana University School of Medicine, Indianapolis, United States of America

⁵Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, United States of America

⁶Department of Pathobiology, University of Guelph, Ontario Veterinary College, Guelph, Canada

⁷Department of Laboratory Medicine, UCSF, San Francisco, United States of America

⁸Division of Radiation Oncology, UCSF, San Francisco, United States of America

⁹Helen Diller Family Comprehensive Cancer, UCSF, San Francisco, United States of America

¹⁰Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Besthesda, United States of America

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¹Division of Pediatric Oncology, UCSF, San Francisco, United States of America

²Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

³UCSF CoLabs, UCSF, San Francisco, United States of America

⁴Center for Computational Biology and Bioinformatics, Department of Medical, Indiana University School of Medicine, Indianapolis, United States of America

⁵Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, United States of America

⁶Department of Pathobiology, University of Guelph, Ontario Veterinary College, Guelph, Canada

⁷Department of Laboratory Medicine, UCSF, San Francisco, United States of America

⁸Division of Radiation Oncology, UCSF, San Francisco, United States of America

⁹Helen Diller Family Comprehensive Cancer, UCSF, San Francisco, United States of America

¹⁰Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Besthesda, United States of America

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¹Division of Pediatric Oncology, UCSF, San Francisco, United States of America

²Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

³UCSF CoLabs, UCSF, San Francisco, United States of America

⁴Center for Computational Biology and Bioinformatics, Department of Medical, Indiana University School of Medicine, Indianapolis, United States of America

⁵Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, United States of America

⁶Department of Pathobiology, University of Guelph, Ontario Veterinary College, Guelph, Canada

⁷Department of Laboratory Medicine, UCSF, San Francisco, United States of America

⁸Division of Radiation Oncology, UCSF, San Francisco, United States of America

⁹Helen Diller Family Comprehensive Cancer, UCSF, San Francisco, United States of America

¹⁰Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Besthesda, United States of America

Find articles by Sweet-Cordero, E. in: PubMed | Google Scholar

An immunosuppressive, macrophage-rich tumor microenvironment (TME) is a barrier to immunotherapy across many cancers including osteosarcoma, where immunotherapy has largely failed. cGAS-STING agonism has been explored to inflame such tumors, yet the mechanisms of STING-mediated TME remodeling remain poorly understood, especially in sarcomas. Using multi-modal single cell analysis, we show that systemic STING agonism in osteosarcoma triggers a myeloid-predominant inflammatory response and rapid tumor necrosis, followed by a T cell-mediated response, immunologic memory, and long-term cure in some models. Within two hours of treatment, STING agonism induces pro-inflammatory interferon programs in tumor-associated macrophages and monocytes, with additional contributions from endothelial cells. Efficacy persists in the absence of tumor-intrinsic STING or IFNAR, confirming that the therapeutic axis resides within the host TME rather than the tumor cell compartment. While cGAS-STING is frequently repressed in human osteosarcoma models of aggressive disease, a STING activation gene signature predicts survival in newly diagnosed patients, suggesting that this pathway is engaged during tumor progression. Together, these data identify an opportunity to exploit the myeloid compartment of osteosarcoma with STING pathway therapies, charting a path forward for engaging the TME to secure long term cure in an aggressive malignancy still treated with highly toxic chemotherapy.

STING agonism orchestrates myeloid-predominant tumor necrosis preceding T cell-dependent regression in osteosarcoma

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STING agonism orchestrates myeloid-predominant tumor necrosis preceding T cell-dependent regression in osteosarcoma

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