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

J Clin Invest. 2019 Jan 2;129(1):137-149. doi: 10.1172/JCI121266. Epub 2018 Nov 19.


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.

Keywords: Brain cancer; Cancer immunotherapy; Chemokines; Immunology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aptamers, Nucleotide / pharmacology
  • Brain Neoplasms / genetics
  • Brain Neoplasms / immunology*
  • Brain Neoplasms / pathology
  • Brain Neoplasms / therapy
  • CD8-Positive T-Lymphocytes
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / immunology*
  • Gene Knockdown Techniques
  • Glioblastoma / genetics
  • Glioblastoma / immunology*
  • Glioblastoma / pathology
  • Glioblastoma / therapy
  • Humans
  • Immunity, Cellular / drug effects
  • Immunity, Cellular / genetics
  • Immunity, Innate*
  • Macrophages / immunology*
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / immunology*
  • Osteopontin / genetics
  • Osteopontin / immunology*
  • Receptors, Vitronectin / genetics
  • Receptors, Vitronectin / immunology


  • Aptamers, Nucleotide
  • Neoplasm Proteins
  • Receptors, Vitronectin
  • SPP1 protein, human
  • Spp1 protein, mouse
  • integrin alphaVbeta5
  • Osteopontin