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

Jun Wei, Anantha Marisetty, Brett Schrand, Konrad Gabrusiewicz, Yuuri Hashimoto, Martina Ott, Zacharia Grami, Ling Yuan Kong, Xiaoyang Ling, Hillary Caruso, Shouhao Zhou, Y. Alan Wang, Gregory N. Fuller, Jason Huse, Eli Gilboa, Nannan Kang, Xingxu Huang, Roel Verhaak, Shulin Li, Amy B. Heimberger

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Article numberCI121266
JournalJournal of Clinical Investigation
Volume129
Issue number1
DOIs
StatePublished - Jan 2 2019

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Osteopontin
Glioblastoma
Macrophages
Glioma
Therapeutics
Chemokines
Small Interfering RNA
Clustered Regularly Interspaced Short Palindromic Repeats
T-Lymphocytes
Survival
Immunoblotting
Integrins
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Osteopontin mediates glioblastoma-associated macrophage infiltration and is a potential therapeutic target. / Wei, Jun; Marisetty, Anantha; Schrand, Brett; Gabrusiewicz, Konrad; Hashimoto, Yuuri; Ott, Martina; Grami, Zacharia; Kong, Ling Yuan; Ling, Xiaoyang; Caruso, Hillary; Zhou, Shouhao; Wang, Y. Alan; Fuller, Gregory N.; Huse, Jason; Gilboa, Eli; Kang, Nannan; Huang, Xingxu; Verhaak, Roel; Li, Shulin; Heimberger, Amy B.

In: Journal of Clinical Investigation, Vol. 129, No. 1, CI121266, 02.01.2019.

Research output: Contribution to journalArticle

Wei, J, Marisetty, A, Schrand, B, Gabrusiewicz, K, Hashimoto, Y, Ott, M, Grami, Z, Kong, LY, Ling, X, Caruso, H, Zhou, S, Wang, YA, Fuller, GN, Huse, J, Gilboa, E, Kang, N, Huang, X, Verhaak, R, Li, S & Heimberger, AB 2019, 'Osteopontin mediates glioblastoma-associated macrophage infiltration and is a potential therapeutic target', Journal of Clinical Investigation, vol. 129, no. 1, CI121266. https://doi.org/10.1172/JCI121266
Wei, Jun ; Marisetty, Anantha ; Schrand, Brett ; Gabrusiewicz, Konrad ; Hashimoto, Yuuri ; Ott, Martina ; Grami, Zacharia ; Kong, Ling Yuan ; Ling, Xiaoyang ; Caruso, Hillary ; Zhou, Shouhao ; Wang, Y. Alan ; Fuller, Gregory N. ; Huse, Jason ; Gilboa, Eli ; Kang, Nannan ; Huang, Xingxu ; Verhaak, Roel ; Li, Shulin ; Heimberger, Amy B. / Osteopontin mediates glioblastoma-associated macrophage infiltration and is a potential therapeutic target. In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 1.
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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.",
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AU - Zhou, Shouhao

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AU - Fuller, Gregory N.

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AU - Gilboa, Eli

AU - Kang, Nannan

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AU - Verhaak, Roel

AU - Li, Shulin

AU - Heimberger, Amy B.

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