Abstract
Glioblastoma (GBM) is an immunologically "cold" tumor that does not respond to current immunotherapy. Here, we demonstrate a fundamental role for the α-isoform of the catalytic subunit of protein phosphatase-2A (PP2Ac) in regulating glioma immunogenicity. Genetic ablation of PP2Ac in glioma cells enhanced double stranded DNA (dsDNA) production and cGAS-type I interferon (IFN) signaling, MHC-I expression, and tumor mutational burden. In co-culture experiments, PP2Ac deficiency in glioma cells promoted dendritic cell (DC) cross presentation and clonal expansion of CD8+ T cells. In vivo, PP2Ac depletion sensitized tumors to immune checkpoint blockade and radiotherapy treatment. Single cell analysis demonstrated that PP2Ac deficiency increased CD8+ T cell, NK cell, and DC accumulation and reduced immunosuppressive tumor associated macrophages. Furthermore, loss of PP2Ac increased IFN signaling in myeloid and tumor cells and reduced expression of a tumor gene signature associated with worse patient survival in TCGA. Collectively, this study establishes a novel role for PP2Ac in inhibiting dsDNA-cGAS-STING signaling to suppress anti-tumor immunity in glioma.
