1. Interrogating glioma-M2 macrophage interactions identifies Gal-9/Tim-3 as a viable target against PTEN -null glioblastoma.
- Author
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Ni X, Wu W, Sun X, Ma J, Yu Z, He X, Cheng J, Xu P, Liu H, Shang T, Xi S, Wang J, Zhang J, and Chen Z
- Subjects
- Cell Line, Tumor, Galectins genetics, Galectins metabolism, Hepatitis A Virus Cellular Receptor 2 metabolism, Humans, Macrophages metabolism, Neovascularization, Pathologic metabolism, PTEN Phosphohydrolase genetics, PTEN Phosphohydrolase metabolism, Tumor Microenvironment, Glioblastoma drug therapy, Glioblastoma genetics, Glioblastoma metabolism, Glioma drug therapy, Glioma genetics, Glioma metabolism
- Abstract
Genomic alteration can reshape tumor microenvironment to drive tumor malignancy. However, how PTEN deficiency influences microenvironment-mediated cell-cell interactions in glioblastoma (GBM) remains unclear. Here, we show that PTEN deficiency induces a symbiotic glioma-M2 macrophage interaction to support glioma progression. Mechanistically, PTEN -deficient GBM cells secrete high levels of galectin-9 (Gal-9) via the AKT-GSK3β-IRF1 pathway. The secreted Gal-9 drives macrophage M2 polarization by activating its receptor Tim-3 and downstream pathways in macrophages. These macrophages, in turn, secrete VEGFA to stimulate angiogenesis and support glioma growth. Furthermore, enhanced Gal-9/Tim-3 expression predicts poor outcome in glioma patients. In GBM models, blockade of Gal-9/Tim-3 signaling inhibits macrophage M2 polarization and suppresses tumor growth. Moreover, α-lactose attenuates glioma angiogenesis by down-regulating macrophage-derived VEGFA, providing a novel antivascularization strategy. Therefore, our study suggests that blockade of Gal-9/Tim-3 signaling is effective to impair glioma progression by inhibiting macrophage M2 polarization, specifically for PTEN -null GBM.
- Published
- 2022
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