IMMU-07. Synergistic STING activation in meningioma neoplastic and immune populations triggers programmed necrosis and modulates the collagen-rich immunosuppressive microenvironment

Abstract Despite recent progress in elucidating the molecular events underlying meningioma aggressiveness, there remain no established adjuvant therapies for tumors that are intractable to surgery and radiation. Using integrated approaches of single-cell RNA/ATAC-seq, spatial multiprotein immunofluorescence, and bulk RNA-seq and methylation profiling, we identify widespread expression of STING across multiple cell populations within the meningioma microenvironment. In contrast to other brain tumors such as glioma, meningioma neoplastic cells exhibited increased chromatin accessibility and promoter hypomethylation, associated with robust STING expression across WHO grades and DNA methylation subgroups. Treatment of freshly resected human meningiomas with the STING agonist 8803 induced direct cytotoxicity within 72 hours, even after removal of CD45+ immune cells. Pharmacologic inhibitors and transcriptional profiling revealed an association of programmed necrotic cell death pathways with 8803 efficacy, including partial dependence on reactive oxygen species production. Proteolytic maturation of the pore-forming protein gasdermin D on meningioma cancer cells contributed to 8803-induced cytotoxicity, and resulted in release of pro-inflammatory damage-associated molecular pattern molecules that further potentiated innate immune cell activation through toll-like receptors. STING activation via 8803 reduced meningioma volume across four preclinical murine models, and significantly improved survival after intracranial tumor treatment. These therapeutic effects were associated with marked immunological tumor infiltration and cytotoxicity, tumor stromal remodeling through macrophage elaborated metalloproteinases, and downregulation of the TIM3 and LAIR1 dominant mechanisms of meningioma-mediated immune suppression. Our results reveal widespread synergistic expression of STING in neoplastic and myeloid populations in meningioma, identify novel mechanisms of STING cytotoxicity in tumor cells, suggest a role for STING activation in degradation of collagen-rich tumor microenvironments, and clarify a new treatment indication for the STING agonist 8803.

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Publication Details

Journal
Neuro-Oncology
Published
2025-11-01
DOI
https://doi.org/10.1093/neuonc/noaf201.0806
Primary Topic
interferon and immune responses
Type
article
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article

IMMU-07. Synergistic STING activation in meningioma neoplastic and immune populations triggers programmed necrosis and modulates the collagen-rich immunosuppressive microenvironment

Ching Man Wai, Kathleen McCortney, Deanna Tiek, Shashwat Tripathi et al.
Neuro-Oncology
interferon and immune responses
article

IMMU-07. Synergistic STING activation in meningioma neoplastic and immune populations triggers programmed necrosis and modulates the collagen-rich immunosuppressive microenvironment

Ching Man Wai, Kathleen McCortney, Deanna Tiek, Shashwat Tripathi, David Ronan Raleigh, Hinda Najem, Craig Horbinski, Leah Billingham, Matthew C. Tate, Nishanth S. Sadagopan, Mark W. Youngblood, Ashley N. Selner, Qiang-Hong Pu, Gustavo M. Cervantes, Jacky T. Yeung, Stephen T. Magill, Michel Kalamarides, Thomas Sears, Rimas V. Lukas, Matthieu Peyre, Caylee Silvers, Roger Stupp, Maciej S. Lesniak, Jawad Fares, Adam M. Sonabend, David M. Ashley, Alexander H. Stegh, Michael P. Hagan, Michael A. Curran, Pouya Jamshidi, Jason Miska, Gavin P. Dunn, Daniel Jay Brat, Amy B. Heimberger, Alicia Steffens, Jared T. Ahrendsen, Lisa Hurley, Rahul Kishore Chaliparambil, Peng Zhang, Wenxia Wang, Daniel Eduardo Oyon, Abrar Choudhury, L. Sanchez Fernandez, Mateo Gomez, Harrshavasan T. S. Congivaram, James P. Chandler, Joy Trybula
article en

Abstract

Abstract Despite recent progress in elucidating the molecular events underlying meningioma aggressiveness, there remain no established adjuvant therapies for tumors that are intractable to surgery and radiation. Using integrated approaches of single-cell RNA/ATAC-seq, spatial multiprotein immunofluorescence, and bulk RNA-seq and methylation profiling, we identify widespread expression of STING across multiple cell populations within the meningioma microenvironment. In contrast to other brain tumors such as glioma, meningioma neoplastic cells exhibited increased chromatin accessibility and promoter hypomethylation, associated with robust STING expression across WHO grades and DNA methylation subgroups. Treatment of freshly resected human meningiomas with the STING agonist 8803 induced direct cytotoxicity within 72 hours, even after removal of CD45+ immune cells. Pharmacologic inhibitors and transcriptional profiling revealed an association of programmed necrotic cell death pathways with 8803 efficacy, including partial dependence on reactive oxygen species production. Proteolytic maturation of the pore-forming protein gasdermin D on meningioma cancer cells contributed to 8803-induced cytotoxicity, and resulted in release of pro-inflammatory damage-associated molecular pattern molecules that further potentiated innate immune cell activation through toll-like receptors. STING activation via 8803 reduced meningioma volume across four preclinical murine models, and significantly improved survival after intracranial tumor treatment. These therapeutic effects were associated with marked immunological tumor infiltration and cytotoxicity, tumor stromal remodeling through macrophage elaborated metalloproteinases, and downregulation of the TIM3 and LAIR1 dominant mechanisms of meningioma-mediated immune suppression. Our results reveal widespread synergistic expression of STING in neoplastic and myeloid populations in meningioma, identify novel mechanisms of STING cytotoxicity in tumor cells, suggest a role for STING activation in degradation of collagen-rich tumor microenvironments, and clarify a new treatment indication for the STING agonist 8803.

Neuro-OncologyVol. 27(Supplement_5)
Northwestern University (US), Brigham and Women's Hospital (US), The University of Texas MD Anderson Cancer Center (US), City College of San Francisco (US), Duke University (US), Washington University in St. Louis (US), Yale University (US), Assistance Publique – Hôpitaux de Paris (FR), Northwestern University (PH)
Openalex Percentile: Top 64%
interferon and immune responses
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