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

作者：Jun Wei, Anantha Marisetty, Brett Schrand, Konrad R. Gabrusiewicz, Yuuri Hashimoto, Martina Ott, Zacharia A. Grami, Ling‐Yuan Kong, Xiaoyang Ling, Hillary G. Caruso, Shouhao Zhou, Y. Alan Wang, Gregory N. Fuller, Jason T. Huse, Eli Gilboa, Nannan Kang, Xingxu Huang, Roel G.W. Verhaak, Shulin Li, Amy B. Heimberger · 发表于：Journal of Clinical Investigation · 年份：2018 · DOI：10.1172/jci121266 · 被引用次数：415 · 研究领域：Bone and Dental Protein Studies、Cancer Research and Treatments、Immune cells in cancer

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 medi...