Osteopontin mediates glioblastoma-associated macrophage infiltration and is a potential therapeutic target.
Document Type
Article
Publication Date
1-2-2019
Keywords
JGM
JAX Source
J Clin Invest 2019 Jan; 129(1):137-149
Volume
129
Issue
1
First Page
137
Last Page
149
ISSN
1558-8238
PMID
30307407
DOI
https://doi.org/10.1172/JCI121266
Grant
CA16672,CA120895,CA127001,1S10OD016167
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.
Recommended Citation
Wei J,
Marisetty A,
Schrand B,
Gabrusiewicz K,
Hashimoto Y,
Ott M,
Grami Z,
Kong L,
Ling X,
Caruso H,
Zhou S,
Wang Y,
Fuller G,
Huse J,
Gilboa E,
Kang N,
Huang X,
Verhaak R,
Li S,
Heimberger A.
Osteopontin mediates glioblastoma-associated macrophage infiltration and is a potential therapeutic target. J Clin Invest 2019 Jan; 129(1):137-149