Dataset Information


Osteopontin mediates glioblastoma-associated macrophage infiltration and is a potential therapeutic target.

ABSTRACT: Glioblastoma is highly enriched with macrophages, and osteopontin (OPN) expression levels correlate with glioma grade and the degree of macrophage infiltration; thus, we studied whether OPN plays a crucial role in immune modulation. Quantitative PCR, immunoblotting, and ELISA were used to determine OPN expression. Knockdown of OPN was achieved using complementary siRNA, shRNA, and CRISPR/Cas9 techniques, followed by a series of in vitro functional migration and immunological assays. OPN gene-deficient mice were used to examine the roles of non-tumor-derived OPN on survival of mice harboring intracranial gliomas. Patients with mesenchymal glioblastoma multiforme (GBM) show high OPN expression, a negative survival prognosticator. OPN is a potent chemokine for macrophages, and its blockade significantly impaired the ability of glioma cells to recruit macrophages. Integrin αvβ5 (ITGαvβ5) is highly expressed on glioblastoma-infiltrating macrophages and constitutes a major OPN receptor. OPN maintains the M2 macrophage gene signature and phenotype. Both tumor-derived and host-derived OPN were critical for glioma development. OPN deficiency in either innate immune or glioma cells resulted in a marked reduction in M2 macrophages and elevated T cell effector activity infiltrating the glioma. Furthermore, OPN deficiency in the glioma cells sensitized them to direct CD8+ T cell cytotoxicity. Systemic administration in mice of 4-1BB-OPN bispecific aptamers was efficacious, increasing median survival time by 68% (P < 0.05). OPN is thus an important chemokine for recruiting macrophages to glioblastoma, mediates crosstalk between tumor cells and the innate immune system, and has the potential to be exploited as a therapeutic target.


PROVIDER: S-EPMC6307970 | BioStudies | 2019-01-01


REPOSITORIES: biostudies

Similar Datasets

1000-01-01 | S-EPMC4271080 | BioStudies
2020-01-01 | S-EPMC7293068 | BioStudies
2017-01-01 | S-EPMC5206721 | BioStudies
2020-01-01 | S-EPMC7244085 | BioStudies
2020-01-01 | S-EPMC7041103 | BioStudies
2015-01-01 | S-EPMC4741750 | BioStudies
2019-01-01 | S-EPMC6561349 | BioStudies
2013-01-01 | S-EPMC3776729 | BioStudies
2021-01-01 | S-EPMC7937290 | BioStudies
2018-01-01 | S-EPMC6204912 | BioStudies