Abstract
Interactions between tumor cells and tumor-associated macrophages (TAMs) are critical for glioblastoma progression. The TAMs represent up to 30% of the glioblastoma mass. The role of TAMs in tumor progression and in the mechanisms underlying tumor growth remain unclear. Using an in vitro model resembling the crosstalk between macrophages and glioblastoma cells, we show that glioblastoma-derived exosomes (GBex) reprogram M1 (mediate pro-inflammatory function) and M2 (mediate anti-inflammatory function) macrophages, converting M1 into TAMs and augmenting pro-tumor functions of M2 macrophages. In turn, these GBex-reprogrammed TAMs, produce exosomes decorated by immunosuppressive and tumor-growth promoting proteins. TAM-derived exosomes disseminate these proteins in the tumor microenvironment (TME) promoting tumor cell migration and proliferation. Mechanisms underlying the promotion of glioblastoma growth involved Arginase-1+ exosomes produced by the reprogrammed TAMs. A selective Arginase-1 inhibitor, nor-NOHA reversed growth-promoting effects of Arginase-1 carried by TAM-derived exosomes. The data suggest that GBex-reprogrammed Arginase-1+ TAMs emerge as a major source of exosomes promoting tumor growth and as a potential therapeutic target in glioblastoma.
Highlights
Glioblastoma, called grade IV glioma, represents about 50% of all brain neoplasms [1]
Brain tumors effectively recruit immune cells derived from the blood, up to 30% of the glioblastoma mass consists of macrophages, suggesting that that these cells are involved in the promotion of tumor progression and in chemoresistance [5,6]
Our findings reveal a novel mechanism for macrophage-glioblastoma crosstalk in the tumor microenvironment (TME) and provide additional evidence for the important role exosomes play in reprogramming the TME and regulating immune cell-tumor cell communication
Summary
Glioblastoma, called grade IV glioma, represents about 50% of all brain neoplasms [1]. Interactions between tumor cells and tumor-infiltrating macrophages have been reported to be important for disease outcome in several types of cancer, including glioblastoma [4]. Brain tumors effectively recruit immune cells derived from the blood, up to 30% of the glioblastoma mass consists of macrophages, suggesting that that these cells are involved in the promotion of tumor progression and in chemoresistance [5,6]. Cellular plasticity has been shown to be a characteristic feature of macrophages and microglia [7]. In the tumor microenvironment (TME), macrophages are known to participate in numerous cellular functions, including cell proliferation, migration, angiogenesis, and metastasis [9]. Mechanisms essential for the education of naïve macrophages to tumor-associated macrophages (TAMs) with tumor-promoting functions remain unclear
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