Abstract LB-207: PI3Kγ inhibition suppresses glioblastoma tumorigenicity through disruption of an IL11-STAT3-MYC signaling axis between microglia and glioblastoma

Abstract

Abstract While 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 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. We show that the growth stimulatory effects of microglia can be recapitulated using conditioned media derived 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. Further, 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 level in microglia was significantly higher than in tumor cells. In vitro and in vivo experiments demonstrated that IL11 was necessary and sufficient for enhancement of glioblastoma tumorigenicity. IL11 induced activation of a STAT3-MYC signaling axis in tumor cells, which upregulates the 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, PI3Kγ inhibitor suppressed tumorigenicity in vivo by reducing microglia density and IL11 release in murine glioblastoma GL261 tumors. These effects were recapitulated when GL261 was implanted into PI3Kγ-/- mice. Importantly, ectopic expression IL11 reversed the tumor-suppressive effect of PI3Kγ inhibitor. The anti-glioblastoma effects of PI3Kγ inhibitor 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. Citation Format: Jie Li, Megan M. Kaneda, Jiangfei Wang, Kunal Patel, Johnny Akers, Valya Ramakrishnan, Tao Jiang, Bob S. Carter, Judith A. Varner, Clark C. Chen. PI3Kγ inhibition suppresses glioblastoma tumorigenicity through disruption of an IL11-STAT3-MYC signaling axis between microglia and glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-207. doi:10.1158/1538-7445.AM2017-LB-207