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

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.

Duke Scholars

Author David Michael Ashley Neurosurgery