Tumor-Associated Macrophage IL-1beta Promotes GPD2 Activation, Glycolysis, and Tumorigenesis in Glioma Cells.

Tumor-immune crosstalk within the tumor microenvironment (TME) participates at all stages of tumorigenesis. Tumor-associated M2 macrophages play a central role in tumor development, but the molecular underpinnings are not fully elucidated. We demonstrated that M2 macrophages produce interleukin 1beta (IL-1beta), which activates phosphorylation of the glycolytic enzyme glycerol-3-phosphate dehydrogenase (GPD2) at threonine 10 (GPD2 pT10) via PI3K-mediated activation of protein kinase-delta (PKCdelta) in glioma cells. GPD2 pT10 enhanced its substrate affinity and increased the catalytic rate of glycolysis in glioma cells. Inhibiting PKCdelta or GPD2 pT10 in glioma cells or blocking IL-1beta generated by macrophages attenuated the glycolytic rate and proliferation of glioma cells. Furthermore, human glioblastoma (GBM) tumor GPD2 pT10 levels were positively correlated with tumor p-PKCdelta and IL-1beta levels as well as intratumoral macrophage recruitment, tumor grade, and GBM patient survival. These results reveal a novel tumorigenic role for M2 macrophages in the TME. Additionally, these findings suggest possible treatment strategies for glioma patients via blockade of cytokine crosstalk between M2 macrophages and glioma cells.