STING activation induces cytotoxic and immune responses in meningiomas via inflammatory cell death pathways
Abstract
Abstract Meningiomas are common tumors of the central nervous system that are typically treated with surgery or radiation, but lack established systemic therapies. Activation of the stimulator of interferon genes pathway with an agonist such as 8803 can trigger anti-tumor immune responses. Using integrated molecular approaches, here we show that this pathway is targetable in both neoplastic and immune populations within the meningioma microenvironment. Meningioma tumor cells exhibit promoter hypomethylation and increased chromatin accessibility of the STING genomic locus, associated with robust expression of this gene. Treatment of diverse patient meningiomas ex vivo with 8803 induces direct tumor cytotoxicity through inflammatory cell death pathways, including induction of gasdermin D membrane pore formation. Release of necrotic tumor debris triggered by 8803 activates macrophages and upregulates matrix metalloproteinase production, facilitating degradation of extra-cellular collagen. Injection of preclinical meningiomas with 8803 induces survival benefits, including in an immunocompetent orthotopic setting, through remodeling of the tumor microenvironment, immune infiltration, and downregulation of tumor-mediated immune suppression, thereby nominating 8803 for treatment consideration in meningiomas.
Article Details
Authors (47)
Mark W. Youngblood
Shashwat Tripathi
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University
Hinda Najem
Harrshavasan Congivaram
Mateo Gomez
Thomas K. Sears
Lisa Hurley
Leah K. Billingham
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University
Caylee Silvers
Wenxia Wang
Deanna Tiek
Nishanth Sadagopan
Rahul Chaliparambil
Qianyi Pu
Ching Man Wai
Abrar Choudhury
Alicia Steffens
Kathleen McCortney
Gustavo Ignacio Vazquez Cervantes
Daniel Oyon
Luis Fernandez
Ashley Selner
Jawad Fares
Matthew Hagan
S. Joy Trybula
Jacky Yeung
Matthieu Peyre
Michel Kalamarides
Peng Zhang
Alexander H. Stegh
Department of Neurological Surgery, The Brain Tumor Center, Washington University School of Medicine, Alvin J. Siteman Comprehensive Cancer Center
David M. Ashley
Craig M. Horbinski
Jared T. Ahrendsen
Department of Pathology
Pouya Jamshidi
Daniel J. Brat
Department of Pathology, Northwestern Medicine Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine
Rimas V. Lukas
Roger Stupp
Maciej S. Lesniak
Adam M. Sonabend
Gavin P. Dunn
Massachusetts General Hospital Cancer Center Boston Massachusetts USA
James P. Chandler
Matthew C. Tate
Stephen T. Magill
Jason Miska
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University
Michael A. Curran
David R. Raleigh
Amy B. Heimberger