OS06.7 PI-3Kγ inhibition suppresses glioblastoma tumorigenicity through disruption of an IL11-STAT3-MYC signaling axis between microglia and glioblastoma

AbstractWhile mutations in isocitrate dehydrogenase (IDH) gene are associated with favorable prognosis in glioblastoma patients, the biologic basis for favorable survival in patients with wild-type IDH (wtIDH) glioblastoma remains poorly understood. We identified that an inflammatory gene signature whose expression inversely correlated with patient survival in three independent, wtIDH glioblastoma cohorts (The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and REMEBRANDT). Systematic analysis of the inflammatory infiltrates of the glioblastoma microenvironment revealed microglia as the predominant cell type driving this survival association. The pro-tumorgenic effects of microglia can be recapitulated using conditioned media derived from microglia. We cross-referenced proteomic profile of microglia conditioned media with the TCGA and the CGGA to identify constituent soluble factors with survival association and identified IL11. In both clinical datasets, increased IL11 expression was associated with shortened survival. Moreover, IL11 expression closely correlated with the survival-associated inflammatory signature in both TCGA and CGGA glioblastomas. IL11 mRNA and protein expression are elevated in clinical glioblastoma specimen relative to the surrounding cerebrum. Analysis of samples secured from three unrelated patients revealed that IL11 expression was largely found in the microglia fraction. and experiments demonstrate that IL11 was necessary and sufficient for enhancement of glioblastoma tumorigenicity. Microglia released IL11 induced activation of a STAT3-MYC signaling axis in glioblastoma cells, which ultimately lead to up-regulation of genes required for glioblastoma tumorigenicity, including OLIG2, SOX2, and POU3F2. PI3Kγ activation in myeloid-derived cells, including microglia, is essential for its trafficking into the tumor microenvironment. We hypothesized that PI3Kγ inhibition or inactivation should impede microglia trafficking to the glioblastoma microenvironment and suppress tumorigenicity. Supporting our hypothesis, treatment with the PI3Kγ, TG100-115, suppressed glioblastoma tumorigenicity by reduced microglia density and IL11 release in the glioblastoma microenvironment. These effects were recapitulated when murine glioblastoma GL261 were implanted into p110γ mice. Importantly, ectopic expression IL11 in GL261 reversed the tumor-suppressive effect of TG100-115. The anti-glioblastoma effects of TG100-115 were enhanced by temozolomide, the standard of care chemotherapy for glioblastoma. These results suggest microglia is a mediator of clinical glioblastoma survival and disruption of microglia-glioblastoma interaction as potential therapeutic strategy.