Insights in the immunobiology of glioblastoma.

Glioblastoma, a grade IV astrocytoma, is considered as the most malignant intracranial tumor, characterized by poor prognosis and therapy resistance. Tumor heterogeneity that often leads to distinct functional phenotypes contributes to glioblastoma (GB) indispensable growth and aggressiveness. The complex interaction of neoplastic cells with tumor microenvironment (TME) along with the presence of cancer stem-like cells (CSCs) largely confers to extrinsic and intrinsic GB heterogeneity. Recent data indicate that glioma cells secrete a variety of soluble immunoregulatory factors to attract different cell types to TME including astrocytes, endothelial cells, circulating stem cells, and a range of immune cells. These further induce a local production of cytokines, chemokines, and growth factors which upon crosstalk with extracellular matrix (ECM) components reprogram immune cells to inflammatory or anti-inflammatory phenotypes and manipulate host's immune response in favor of cancer growth and metastasis. Herein, we provide an overview of the immunobiologic factors that orchestrate the complex network of glioma cells and TME interactions in an effort to identify potential therapeutic targets for GB malignancy. Current therapeutic schemes and advances in targeting GB-TME crosstalk are further discussed. KEY MESSAGES: • Intrinsic and extrinsic tumor heterogeneity affects GB growth and aggressiveness. • GB cells secrete growth factors and chemoattractants to recruit immune cells to TME. • GAMs are a critical cell type in promoting GB growth. • GAMs change from pro-inflammatory, anti-tumor M1 phenotype to pro-tumorigenic M2. • Novel therapeutic agents target the crosstalk of neoplastic cells with TME.